Nitrogenous heterocyclic substituted quinoline compounds

ABSTRACT

The present invention relates to nitrogen-containing heterocyclic quinoline compounds and pharmaceutically acceptable salts thereof which have inhibitory activity on the phosphorylation of kinases, which inhibits the activity of such kinases. The invention is also related to a method of inhibiting kinases and treating disease states in a mammal by inhibiting the phosphorylation of kinases. More particularly, the present invention provides nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof which inhibit phosphorylation of a PDGF receptor to hinder abnormal cell growth and cell wandering, and a method for preventing or treating cell-proliferative diseases such as arteriosclerosis, vascular reobstruction, cancer and glomerulosclerosis.

RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. 119(e)to U.S. Provisional Application No. 60/273,951 filed on Mar. 8, 2001which is herein incorporated in its entirety by reference.

FIELD OF INVENTION

The present invention relates to nitrogen-containing heterocyclicquinoline compounds and pharmaceutically acceptable salts thereof whichhave inhibitory activity on the phosphorylation of kinases, whichinhibits the activity of such kinases. The invention is also related toa method of inhibiting kinases and treating disease states in a mammalby inhibiting the phosphorylation of kinases.

BACKGROUND OF THE INVENTION

The PDGF receptor-family of tyrosine kinases are known to act asaggravating signals for cell-proliferative diseases such asarteriosclerosis, vascular reobstruction after percutaneous coronaryangioplasty and bypass operation, cancer, glomerulonephritis,glomerulosclerosis, psoriasis and articular rheumatism. See Cell, 46:155-169 (1986); Science, 253:1129-1132 (1991); Nippon Rinsho (JapaneseJ. of Clinical Medicine), 50: 3038-3045 (1992); Nephrol Dial Transplant,10: 787-795 (1995); Kidney International, 43 (Suppl. 39): 86-89 (1993);Journal of Rheumatology, 21: 1507-1511 (1994); Scandinavian Journal ofImnmunology, 27: 285-294 (1988), Journal of Clinical Oncology, 29-47(1999), etc.

Certain 3-cyanoquinolines are known to be inhibitors of protein tyrosinekinases and are described in U.S. Pat. No. 6,002,008. More specifically,certain 3-cyanoquinolines are inhibitors of MEK (MAPKK), as described inBioorg. & Med. Chem. Lett., 10: 2825-2828 (2000) and WO 0068201; as srctyrosine kinase inhibitors as described in Bioorg. & Med. Chem. Lett.,10: 2477-2480 (2000); and as EGF-receptor kinase inhibitors as describedin J. Med. Chem., 43: 3244-3256 (2000).

Quinoline derivatives having benzodiazepin receptor agonist activity aredescribed in Pharmacology Biochemistry and Behavior, 53: 87-97 (1996)and European Journal of Medicinal Chemistry, 31: 417-425 (1996), andquinoline derivatives which are useful as anti-parasite agents aredescribed in Indian Journal of Chemistry, 26B: 550-555 (1987).

Inhibitors of phosphorylation of PDGF receptor-family tyrosine kinasesso far known include bismono- and bicyclic aryl compounds and heteroarylcompounds (WO 92/20642), quinoxaline derivatives. Cancer Research, 54:6106 (1994), pyrimidine derivatives (Japanese Published UnexaminedPatent Application No. 87834/94), phenylaminopyrimidine derivatives(EP-0564409-A1, WO-09509847 and U.S. Pat. No. 5,521,184) anddimethoxyquinoline derivatives. Abstracts of the 16th Annual Meeting ofthe Pharmaceutical Society of Japan (Kanazawa) (1996), 2, p. 275, 29(C2)15-2.

SUMMARY OF THE INVENTION

The invention is directed to nitrogen-containing heterocyclic compoundsand pharmaceutically acceptable salts thereof which have inhibitoryactivity on the phosphorylation of kinases, which inhibits the activityof the kinases. More particularly, important kinase inhibition accordingto the invention is of receptor tyrosine kinases includingplatelet-derived growth factor (PDGF) receptor, Flt3, CSF-1R, c-kit,epidermal growth factor receptor (EGRF), fibroblast growth factor (FGF),vascular endothelial growth factor receptor (VEGFR) and others. Anotherclass of kinase inhibition according to the invention is inhibitoryactivity nonreceptor tyrosine kinases including src and abl, and thelike. A third class of kinase inhibition according to the invention isinhibitory activity toward serine/threonine kinases, including suchkinases as MAPK, MEK and cyclin dependent kinases (CDKs) that mediatecell prolifetation, AKT and CDK such that mediate cell survival and NIKthat regulate inflammatory responses. Inhibition of such kinases can beused to treat diseases involving cell survival, proliferation andmigration, including cardiovascular disease, such as arteriosclerosisand vascular reobstruction, cancer, glomerulosclerosis fibrotic diseasesand inflammation, as well as the general treatment of cell-proliferativediseases.

Another aspect of the present invention relates to compounds andpharmaceutically acceptable salts thereof which inhibit or preventphosphorylation of at least one PDGF receptor-family member. Such PDGFreceptor-family kinase inhibitors can hinder abnormal cell growth andcell wandering, and thus such compounds are useful for the prevention ortreatment of cell-proliferative diseases such as arteriosclerosis,vascular reobstruction, cancer and glomerulosclerosis.

Another aspect of the invention relates to nitrogen-containingheterocyclic quinoline compounds represented by general formula (I):

wherein:

-   V is a member selected from the group consisting of an oxygen atom,    a sulfur atom and ═N—CN;-   W is 1,4-piperazinediyl or 1,4-homopiperazinedlyl in which carbons    on the ring may be optionally substituted by 0 to 4 C₁ to C₁₆ alkyl    groups which may be the same or different and each alkyl group my be    independently substituted by 0-4 R^(a) groups;    -   wherein R^(a) is a member selected from the group consisting of        halo, haloalkyl, —CN, —CN(R^(b), R^(c)),—N(R^(b), R^(c)),        —C(═O)—N(R^(b), R^(c)), —NO₂, —SO₂N(R^(b), R^(c)), —SO₂R^(b),        —(CH₂)_(m)NR^(b)R^(c), —(CH₂)_(m)—C(═NR^(b))—R^(c),        —(CH₂)_(m)—C(═NR^(b))—N (R^(b),R^(c)),        —(CH₂)_(m)—N(R^(b))—C(═NR^(b))—N(R^(b),R^(c)), —(CH₂)_(m),        —NR^(b)—C₃₋₆heterocyclics, —C₁₋₄alkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CF₃,        —OR^(b), and a 5-6 membered heterocyclic system containing from        1-4 heteroatoms selected from N, O and S, wherein from 1-4        hydrogen atoms on the heterocyclic system may be independently        replaced with a member selected from the group consisting of        halo, haloalkyl, —CN, CN(R^(b), R^(c)),—N(R^(b), R^(c)),        —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;        -   wherein            -   m is 0 to 2,            -   R^(b) and R^(c) are each independently a member selected                from the group consisting of —H, —OR^(d), —N(—R^(d),                —R^(e)), —C₁₋₄alkyl —C₂₋₆alkenyl, —C₂₋₆alkynyl,                —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl,                —C₀₋₄alkylphenyl and —C₀₋₄alkylnaphthyl, wherein from                the ring atoms of the phenyl and naphthyl moieties may                be independently replaced with a member selected from                the group consisting of halo, haloalkyl, —C₁₋₄alkyl,            -   —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,                —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂, and R^(d) and                R^(e) are each independently a member selected from the                group consisting of —C₁₋₄alkyl, —C₂₋₆alkenyl,                —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl;            -   or R^(b) and R^(c) taken together with a carbon atom or                nitrogen atom to which they are attached can form a 3-8                membered cycloalkyl or a heterocyclic ring system,                wherein the heterocyclic ring system may have from 3 to                10 ring atoms, with 1 to 2 rings being in the ring                system and contain from 1-4 heteroatoms selected from N,                O and S, wherein from 1-4 hydrogen atoms on the                heterocyclic ring system may be independently replaced                with a member selected from the group consisting of                halo, haloalkyl, —CN, —CN(R^(b), R^(c)), —N(R^(b),                R^(c)), —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,                —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;-   X is a member selected from the group consisting of:-   H, T—Z, F and Cl; wherein Z is OH, CN or CHO;-   R¹ is a member selected from the group consisting of:    -   a hydrogen atom, a C₁ to C₁₆ alkyl group which may be optionally        substituted by 0 to 4 R^(1a) groups, a C₂ to C₁₆ alkenyl group        which may be optionally substituted by 0 to 4 R^(1a) groups, a        C₂ to C₁₆ cycloalkyl group which may be optionally substituted        by 0 to 4 R^(1a) groups, a partially or fully saturated        monocyclic or bicyclic heterocyclic ring system having 5 to 10        ring atoms and 1 to 4 of the ring atoms is a member selected        from the group consisting of O, S, and N, wherein the        heterocylic ring system may be optionally substituted by 0 to 4        R^(1a) groups, a heteroaryl ring system having 5 to 10 ring        atoms and 1 to 4 of the ring atoms is a member selected from the        group consisting of O, S, and N, wherein the heterocylic ring        system may be optionally substituted by 0 to 4 R^(1a) groups,        and a heteroarylalkyl group having from 5 to 10 ring atoms and 1        to 16 carbon atoms in the alkyl portion, and 1 to 4 of the ring        atoms is a member selected from the group consisting of O, S,        and N, wherein the heteroaryl ring may be optionally substituted        by 0 to 4 R^(1a) groups, wherein R^(1a) is a member selected        from the group consisting of halo, haloalkyl, —CN, —CN(R^(b),        R^(c)),—N(R^(b), R^(c)), —C(═O)—N(R^(1b), R^(1c)), —NO₂,        —SO₂N(R^(1b), R^(1c)), —SO₂R^(1b), —(CH₂)_(n)NR^(1b)R^(1c),        —(CH₂)_(n)—C(═NR^(1b))—R^(1c), —(CH₂)_(n)—C(═NR^(1b))—N(R^(1b),        R^(1c)), —(CH₂)_(n)—N(R^(1b))—C(═NR^(1b))—N(R^(1b), R^(1c)),        —(CH₂)_(n)—NR^(1b)—C₃₋₆heterocyclics, —C₁₋₄alkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CF₃,        —OR^(1b), and a 5-6 membered heterocyclic system containing from        1-4 heteroatoms selected from N, O and S, wherein from 1-4        hydrogen atoms on the heterocyclic system may be independently        replaced with a member selected from the group consisting of        halo, haloalkyl, —CN, —N(R^(b), R^(c)),—N(R^(b), R^(c)),        —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;    -   wherein        -   n is 0 to 2,        -   R^(1b) and R^(1c) are each independently a member selected            from the group consisting of —H, —OR^(1d), —N(—R^(1d),            —R^(1e)), —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,            —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl            and —C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on            the ring atoms of the phenyl and naphthyl moieties may be            independently replaced with a member selected from the group            consisting of halo, haloalkyl, —C₁₋₄alkyl, —C₂₋₆alkenyl,            —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl,            —CN, and —NO₂, and R^(1d) and R^(1e) are each independently            a member selected from the group consisting of —C₁₋₄alkyl,            —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,            —C₀₋₄alkylC₃₋₈cycloalkyl;        -   or R^(b) and R^(c) taken together with a carbon atom or            nitrogen atom to which they are attached can form a 3-8            membered cycloalkyl or a heterocyclic ring system, wherein            the heterocyclic ring system may optionally have from 3 to            10 ring atoms, with 1 to 2 rings being in the ring system            and contain from 1-4 heteroatoms selected from N, O and S,            wherein from 1-4 hydrogen atoms on the heterocyclic ring            system may be independently replaced with a member selected            from the group consisting of halo, haloalkyl, —CN,            —CN(R^(b), R^(c)),—N(R^(b), R^(c)), —C₁₋₄alkyl,            —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,            —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;-   R² is a member selected from the group consisting of:    -   (a) a hydrogen atom, a C₁ to C₁₆ alkyl group which may be by 0        to 4 R^(2a) groups, a C₂ to C₁₆ alkenyl group which may be by 0        to 4 R^(2a) groups, a C₂ to C₁₆ cycloalkyl group which may be by        0 to 4 R^(2a) groups, wherein R^(2a) is a member selected rom        the group consisting of halo, haloalkyl, —CN(R^(b), R^(c)),        —CN(R^(b), R^(c)), —C(═O)—N(R^(2b), R^(2c)), —NO₂, —SO₂N(R^(2b),        R^(2c)), —SO₂R^(2b), —(CH₂)_(p)NR^(2b)R^(2c),        —(CH₂)_(p)—C(═NR^(2b))—R^(2c),        —(CH₂)_(p)—C(═NR^(2b))—N(R^(2b),R^(2c)),        —(CH₂)_(p)—N(R^(2b))—C(═NR^(2b))—N(R^(2b), R^(2c)),        —(CH₂)_(p)—NR^(2b)—C₃₋₆heterocyclics, —C₁₋₄alkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cloalkyl, —CF₃,        —OR^(1b), and a 5-6 membered heterocyclic system containing from        1-4 heteroatoms selected from N, O and S, wherein from 1-4        hydrogen atoms on the heterocyclic system may be independently        replaced with a member selected from the group consisting of        halo, —CN, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;    -   wherein        -   p is 0 to 2,        -   R^(2b) and R^(2c) are each independently a member selected            from the group consisting of —H, —OR^(2d), —N(—R^(2d),            —R^(2e)), —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,            —C₃₋₈cycloalkyl, —CO₄alkylC₃₋₈cycloalkyl, —CO₄alkylphenyl            and —CO₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on            the ring atoms of the phenyl and naphthyl moieties may be            independently replaced with a member selected from the group            consisting of halo, haloalkyl, —C₁₋₄alkyl,        -   —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,            —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂, and R^(2d) and            R^(2c) are each independently a member selected from the            group consisting of —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,            —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl;        -   or R^(2b) and R^(2c) taken together with a carbon atom or            nitrogen atom to which they are attached can form a 3-8            membered cycloalkyl or a heterocyclic ring system, wherein            the heterocyclic ring system may optionally have from 3 to            10 ring atoms, with 1 to 2 rings being in the ring system            and contain from 1-4 heteroatoms selected from N, O and S,            wherein from 1-4 hydrogen atoms on the heterocyclic ring            system may be independently replaced with a member selected            from the group consisting of halo, haloalkyl, —CN,            —CN(R^(b), R^(c)),—N(R^(b), R^(c)), —C₁₋₄alkyl,            —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,            —CO₄alkylC₃₋₈cycloalkyl and —NO₂;    -   (b) phenyl, which is independently substituted with 0-2 R^(2a)        substituents as defined above;    -   (c) naphthyl, which is independently substituted with 0-2 R^(2a)        substituents as defined above; and    -   (d) a monocyclic or fused bicyclic heterocyclic ring system        having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the        ring system are selected from N, O and S, and wherein the ring        system may be optionally substituted with 0-2 R^(2a)        substituents as defined above;    -   (e) —C(═O)—R¹⁰, wherein R¹⁰ is independently a member defined        the same as R¹ above;    -   (f) —S(═O)₁₋₂—R¹¹, wherein R¹¹ is independently a member defined        the same as R¹ above, except that R¹¹ is other than hydrogen;-   R³, R⁴, R⁵ and R⁶ are each independently a member selected from the    group consisting of:    -   (a) a hydrogen atom, a halogen atom, an optionally substituted        alkyl group, a nitro group, a cyano group,    -   (b) —O—R¹², wherein R¹² is independently a member selected from        the group as defined above for R¹⁰;    -   (c) —C(═O)—R¹³, wherein R¹³ is independently a member selected        from the group as defined above for R¹⁰;    -   (d) —SO₂R¹⁴, wherein R¹⁴ is independently a member selected from        the group as defined above for R¹⁰;    -   (e) —N(—R¹⁵, —R¹⁶), wherein each of R¹⁵ and R¹⁶ are        independently a member selected from the group as defined above        for R¹⁰, or R¹⁵ and R¹⁶ are combined together with the adjoining        nitrogen atom to represent an optionally substituted        nitrogen-containing heterocyclic ring system having from 5 to 10        ring atoms, wherein 1-4 ring atoms of the ring system are        selected from N, O and S, and wherein the ring system may be        optionally substituted with 0-2 substituents as defined above        for R^(2a);    -   (f) —SO₂R¹⁷, wherein R¹⁷ is independently a member selected from        the group as defined above for R¹⁰;    -   (g) a radical of the formula:    -   wherein        -   X¹ represents an oxygen atom or a sulfur atom;        -   R¹⁸ is a member selected from the group consisting of            -   (a) a member selected independently from the group as                defined above for R¹⁰;            -   (b) —O—R¹⁹, wherein R¹⁹ is a member selected                independently from the group as defined above for R¹⁰;                or            -   (c) —N(—R²⁰, —R²¹), wherein each of R²⁰ and R²¹ is                independently a member selected independently from the                group as defined above for R¹⁰, or R²⁰ and R²¹ are                combined together with the adjoining nitrogen atom to                represent an optionally substituted nitrogen-containing                heterocyclic ring system having from 5 to 10 ring atoms,                wherein 1-4 ring atoms of the ring system are selected                from N, O and S, and wherein the ring system may be                optionally substituted with 0-2 substituents as defined                above for R^(2a);    -   (h) a radical of the formula:    -   wherein z is an integer from 0 to 2;        -   when z is 0,            -   R²² is a member selected independently from the group as                defined above for R¹⁰;        -   when z is 1,            -   R²² is a member selected independently from the group as                defined above for R¹¹;        -   when z is 2,            -   R²² is a member selected from the group consisting of:            -   (a) a member selected independently from the group as                defined above for R¹¹;            -   (b) —O—R²³, wherein R²³ is a a member selected                independently from the group as defined above for R¹⁰;            -   (c) —N(—R²⁴, R²⁵), wherein R²⁴ and R²⁵ are each                independently a member selected independently from the                group as defined above for R¹⁰, or R²⁴ and R²⁴ are                combined together with the adjoining nitrogen atom to                represent an optionally substituted nitrogen-containing                heterocyclic ring system having from 5 to 10 ring atoms,                wherein 1-4 ring atoms of the ring system are selected                from N, O and S, and wherein the ring system may be                optionally substituted with 0-2 substituents as defined                above for R^(2a);            -   (d) —C(═O)—R²⁶, wherein R²⁶ is a member selected                independently from the group as defined above for R¹⁰,                or R²⁶ is the group —O—R²⁷, wherein R²⁷ is a member                selected independently from the group as defined above                for R¹⁰, or R²⁷ is the group —N(—R²⁸, —R²⁹), wherein R²⁸                and R²⁹ are each independently a member selected                independently from the group as defined above for R¹⁰                or, or R²⁸ and R²⁹ are combined together with the                adjoining nitrogen atom to represent an optionally                susbtituted nitrogen-containing heterocyclic ring system                having from 5 to 10 ring atoms, wherein 1-4 ring atoms                of the ring system are selected from N, O and S, and                wherein the ring system may be optionally substituted                with 0-2 substituents as defined above for R^(2a); and                wherein any two of R³, R⁴, R⁵ and R⁶ attached to                adjoining carbons taken together with the carbon atom to                which they are attached form a ring structure which is a                member selected from the following:    -   (a) a 5 to 6 membered saturated heterocyclic ring having two        oxygen ring atoms interrupted by one or two carbons,        respectively;    -   (b) a or unsubstuted phenyl group; and    -   (c) a heterocyclic ring which is a member selected from the        following group:        -   wherein:        -   A is an oxygen atom or a sulfur atom;        -   Q¹ is a member selected from the group consisting of:            -   (a) the group as defined above for R¹⁰; or            -   (b) —N(—R³¹, —R³²), wherein R³¹ and R³² are each                independently a member selected independently from the                group as defined above for R¹⁰;            -   —O—R³³ or —S—R³³, wherein R³³ is a member selected                independently from the group as defined above for R¹⁰;        -   Q² is a member selected from the group consisting of ═O, ═S,            or ═N—CN; and        -   R³⁰, R³⁴, R³⁵ and R³⁶ are each independently a member            selected from the group as defined above for R¹⁰; and    -   and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

In another aspect, the invention provides nitrogen-containingheterocyclic quinoline compounds represented by general formula (1):

wherein:

-   V is a member selected from the group consisting of an oxygen atom,    a sulfur atom and ═N—CN;-   W is 1,4-piperazinediyl or 1,4-homopiperazinediyl;-   X is a member selected from the group consisting of:-   (—CH₂)₀₋₈—CH₂—OH, (—CH₂)₁₋₈—C(═O)—O(—CH₂)₀₋₈—CH₃, (—CH₂)₁₋₈—C(═O)—H,    (—CH₂)₀₋₈—CN, F and Cl;-   R¹ is a member selected from the group consisting of:    -   a hydrogen atom, a C₁ to C₁₆ alkyl group which may be optionally        substituted by 0 to 4 R^(1a) groups, a C₂ to C₁₆ alkenyl group        which may be optionally substituted by 0 to 4 R^(1a) groups, a        C₂ to C₁₆ cycloalkyl group which may be optionally substituted        by 0 to 4 R^(1a) groups, a partially or fully saturated        monocyclic or bicyclic heterocyclic ring system having 5 to 10        ring atoms and 1 to 4 of the ring atoms is a member selected        from the group consisting of O, S, and N, wherein the        heterocylic ring system may be optionally substituted by 0 to 4        R^(1a) groups, a heteroaryl ring system having 5 to 10 ring        atoms and 1 to 4 of the ring atoms is a member selected from the        group consisting of O, S, and N, wherein the heterocylic ring        system may be optionally substituted by 0 to 4 R^(1a) groups,        and a heteroarylalkyl group having from 5 to 10 ring atoms and 1        to 16 carbon atoms in the alkyl portion, and 1 to 4 of the ring        atoms is a member selected from the group consisting of O, S,        and N, wherein the heteroaryl ring is by 0 to 4 R^(1a) groups,        wherein R^(1a) is a member selected from the group consisting of        halo, haloalkyl, —CN, —CN(R^(b), R^(c)),—N(R^(b), R^(c)),        —C(═O)—N(R^(1b), R^(1c)), —NO₂, —SO₂N(R^(1b), R^(1c)),        —SO₂R^(1b), —(CH₂)_(n)NR^(1b)R^(1c),        —(CH₂)_(n)—C(═NR^(1b))—R^(1c), —(CH₂)_(n)—C(═NR^(1b))—N(R^(1b),        R^(1c)), —(CH₂)_(n)—N(R^(1b))—C(═NR^(1b))—N(R^(1b), R^(1c)),        —(CH₂)_(n)—NR^(1b)—C₃₋₆heterocyclics, —C₁₋₄alkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CF₃,        —OR^(1b), and a 5-6 membered heterocyclic system containing from        1-4 heteroatoms selected from N, O and S, wherein from 1-4        hydrogen atoms on the heterocyclic system may be independently        replaced with a member selected from the group consisting of        halo, haloalkyl, —CN, —CN(R^(b), R^(c)),—N(R^(b), R^(c)),        —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;    -   wherein        -   n is 0 to 2,        -   R^(1b) and R^(1c) are each independently a member selected            from the group consisting of —H, —OR^(1d), —N(—R^(1d),            —R^(1e)), —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,            —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl            and —C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on            the ring atoms of the phenyl and naphthyl moieties may be            independently replaced with a member selected from the group            consisting of halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,            —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂,            and R^(1d) and R^(1e) are each independently a member            selected from the group consisting of —C₁₋₄alkyl,            —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,            —C₀₋₄alkylC₃₋₈cycloalkyl;        -   or R^(b) and R^(c) taken together with a carbon atom or            nitrogen atom to which they are attached can form a 3-8            membered cycloalkyl or a heterocyclic ring system, wherein            the heterocyclic ring system may optionally have from 3 to            10 ring atoms, with 1 to 2 rings being in the ring system            and contain from 1-4 heteroatoms selected from N, O and S,            wherein from 1-4 hydrogen atoms on the heterocyclic ring            system may be independently replaced with a member selected            from the group consisting of halo, haloalkyl, —CN,            —CN(R^(b), R^(c)), —N(R^(b), R^(c)), —C₁₋₄alkyl,            —C₂₋₆alkenyl, —C₂₋₆alkylnyl, —C₃₋₈cycloalkyl,            —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;-   R² is a member selected from the group consisting of:    -   (a) a hydrogen atom, a C₁ to C₁₆ alkyl group which may be        optionally substituted by 0 to 4 R^(2a) groups, a C₂ to C₁₆        alkenyl group which may be by 0 to 4 R^(2a) groups, a C₂ to C₁₆        cycloalkyl group which may be optionally substituted by 0 to 4        R^(2a) groups, wherein R^(2a) is a member selected rom the group        consisting of halo, haloalkyl, —CN, —CN(R^(b), R^(c)), —N(R^(b),        R^(c)), —C(═O)—N(R^(2b), R^(2c)), —NO₂, —SO₂N(R^(2b), R^(2c)),        —SO₂R^(2b), —(CH₂)_(p)NR^(2b)R^(2c),        —(CH₂)_(p)—C(═NR^(2b))—R^(2c),        —(CH₂)_(p)—C(═NR^(2b))—N(R^(2b),R^(2c)),        —(CH₂)_(p)—N(R^(2b))—C(═NR^(2b))—N(R^(2b),R^(2c)),        (CH₂)_(p)—NR^(2b)—C₃₋₆heterocyclics, —C₁₋₄alkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C⁰⁻⁴alkylC₃₋₈cycloalkyl, —CF₃,        —OR^(1b), and a 5-6 membered heterocyclic system containing from        1-4 heteroatoms selected from N, O and S, wherein from 1-4        hydrogen atoms on the heterocyclic system may be independently        replaced with a member selected from the group consisting of        halo, haloalkyl, —CN, —CN(R^(b), R^(c)), —N(R^(b), R^(c)),        —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;        -   wherein            -   p is 0 to 2,            -   R^(2b) and R^(2c) are each independently a member                selected from the group consisting of —H, —OR^(2d),                —N(—R^(2d), —R^(2e)), —C₁₋₄alkyl, —C₂₋₆alkenyl,                —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl,                —C₀₋₄alkylphenyl and —C₀₋₄alkylnaphthyl, wherein from                1-4 hydrogen atoms on the ring atoms of the phenyl and                naphthyl moieties may be independently replaced with a                member selected from the group consisting of halo,                haloalkyl, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,                —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and                —NO₂, and R^(2d) and R^(2c) are each independently a                member selected from the group consisting of —C₁₋₄alkyl,                —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,                —C₀₋₄alkylC₃₋₈cycloalkyl;            -   or R^(2b) and R^(2c) taken together with a carbon atom                or nitrogen atom to which they are attached can form a                3-8 membered cycloalkyl or a heterocyclic ring system,                wherein the heterocyclic ring system may optionally have                from 3 to 10 ring atoms, with 1 to 2 rings being in the                ring system and contain from 1-4 heteroatoms selected                from N, O and S, wherein from 1-4 hydrogen atoms on the                heterocyclic ring system may be independently replaced                with a member selected from the group consisting of                halo, haloalkyl, —CN, —CN(R^(b), R^(c)),—N(R^(b),                R^(c)), —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,                —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;    -   (b) phenyl, which is independently substituted with 0-2 R^(2a)        substituents as defined above;    -   (c) naphthyl, which is independently substituted with 0-2 R^(2a)        substituents as defined above; and    -   (d) a monocyclic or fused bicyclic heterocyclic ring system        having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the        ring system are selected from N, O and S, and wherein the ring        system may be optionally substituted with 0-2 R^(2a)        substituents as defined above;    -   (e) —C(═O)—R¹⁰, wherein R¹⁰ is independently a member defined        the same as R¹ above;    -   (f) —S(═O)₁₋₂—R¹¹, wherein R¹¹ is independently a member defined        the same as R¹ above, except that R¹¹ is other than hydrogen;-   R³, R⁴, R⁵ and R⁶ are each independently a member selected from the    group consisting of:    -   (a) a hydrogen atom, a halogen atom, an optionally substituted        alkyl group, a nitro group, a cyano group, and    -   (b) —O—R¹², wherein R¹² is independently a member selected from        the group as defined above for R¹⁰;    -   and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

In another aspect, the present invention provides compound as describedabove for formula I, represented by formula Ia as follows:

wherein

-   V is a member selected from the group consisting of an oxygen atom    or a sulfur atom; and ═N—CN-   X is a member selected from the group consisting of:-   —(CH₂)₁₋₂—OH, —CH₂—C(═O)—O(—CH₂)₀₋₈—CH₃, —CH₂—C(═O)—H, and    (CH₂)₀₋₁—CN, F, Cl-   Y is a member selected from the group consisting of:-   —CN, —Br, —CF₃, —O—C₁₋₈ alkyl that is independently straight or    branched chained, —O-phenyl, —O-naphthyl, —O-indolyl and    —O-isoquinolinyl;-   R² and R⁴ are each independently a member selected from the group    consisting of:-   —O—CH₃, —O(—CH₂)—CH₃, —O—CH₂—CH═CH₂, —O—CH₂—C≡CH and    —O(CH₂)₂₋₃—R^(2a);-   R^(2a) is a member selected from the group consisting of:-   —OH, —O—CH₃, —O—CH₂—CH₃, —NH₂, —N(—CH₃)₂, —NH(—CH₂-phenyl),    —NH(-Phenyl), —CN    -    and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

In another aspect, the present invention provides compound as describedabove for formula I, represented by formula Ia as follows:

wherein

-   V is a member selected from the group consisting of an oxygen atom    or a sulfur atom;-   X is a member selected from the group consisting of:-   —CN, CO₂Et, CHO, CH₂OH, F, Cl;-   Y is a member selected from the group consisting of:-   —CN, —O—C₁₋₈ alkyl that is independently straight or branched    chained, —O-phenyl, —O-naphthyl, —O-indolyl and —O-isoquinolinyl;-   R² and R⁴ are each different and independently a member selected    from the group consisting of:-   —O—(CH₂—)₀₋₁—CH₃ and —O(—CH₂)₂₋₃—R^(2a);-   R^(2a) is a member selected from the group consisting of:    -    and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

Another aspect of the invention relates to pharmaceutically acceptablesalts of the compounds according to formula (I) include pharmaceuticallyacceptable acid addition salts, metal salts, ammonium salts, organicamine addition salts, amino acid addition salts, etc.

Other aspects, objects, features and advantages of the present inventionwould be apparent to one of ordinary skill in the art from the followingdetailed description illustrating the preferred embodiments of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention and as used herein, thefollowing terms are defined with the following meanings, unlessexplicitly stated otherwise.

The term “alkenyl” refers to a trivalent straight chain or branchedchain unsaturated aliphatic radical. The term “alkinyl” (or “alkynyl”)refers to a straight or branched chain aliphatic radical that includesat least two carbons joined by a triple bond. If no number of carbons isspecified alkenyl and alkinyl each refer to radicals having from 2-12carbon atoms.

The term “alkyl” refers to saturated aliphatic groups includingstraight-chain, branched-chain and cyclic groups having the number ofcarbon atoms specified, or if no number is specified, having up to 12carbon atoms. The term “cycloalkyl” as used herein refers to a mono-,bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms andpreferably 3 to 7 carbon atoms.

As used herein, the terms “carbocyclic ring structure” and “C₃₋₁₆carbocyclic mono, bicyclic or tricyclic ring structure” or the like areeach intended to mean stable ring structures having only carbon atoms asring atoms wherein the ring structure is a or un member selected fromthe group consisting of: a stable monocyclic ring which is aromatic ring(“aryl”) having six ring atoms; a stable monocyclic non-aromatic ringhaving from 3 to 7 ring atoms in the ring; a stable bicyclic ringstructure having a total of from 7 to 12 ring atoms in the two ringswherein the bicyclic ring structure is selected from the groupconsisting of ring structures in which both of the rings are aromatic,ring structures in which one of the rings is aromatic and ringstructures in which both of the rings are non-aromatic; and a stabletricyclic ring structure having a total of from 10 to 16 atoms in thethree rings wherein the tricyclic ring structure is selected from thegroup consisting of: ring structures in which three of the rings arearomatic, ring structures in which two of the rings are aromatic andring structures in which three of the rings are non-aromatic. In eachcase, the non-aromatic rings when present in the monocyclic, bicyclic ortricyclic ring structure may independently be saturated, partiallysaturated or fully saturated. Examples of such carbocyclic ringstructures include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,or tetrahydronaphthyl (tetralin). Moreover, the ring structuresdescribed herein may be attached to one or more indicated pendant groupsvia any carbon atom which results in a stable structure. The term “ ” asused in conjunction with carbocyclic ring structures means that hydrogenatoms attached to the ring carbon atoms of ring structures describedherein may be by one or more of the substituents indicated for thatstructure if such substitution(s) would result in a stable compound.

The term “aryl” which is included with the term “carbocyclic ringstructure” refers to an un or aromatic ring, with one, two or threesubstituents selected from loweralkoxy, loweralkyl, loweralkylamino,hydroxy, halogen, cyano, hydroxyl, mercapto, nitro, thioalkoxy,carboxaldehyde, carboxyl, carboalkoxy and carboxamide, including but notlimited to carbocyclic aryl, heterocyclic aryl, and biaryl groups andthe like, all of which may be optionally. Preferred aryl groups includephenyl, halophenyl, loweralkylphenyl, naphthyl, biphenyl, phenanthrenyland naphthacenyl.

The term “arylalkyl” which is included with the term “carbocyclic aryl”refers to one, two, or three aryl groups having the number of carbonatoms designated, appended to an alkyl group having the number of carbonatoms designated. Suitable arylalkyl groups include, but are not limitedto, benzyl, picolyl, naphthylmethyl, phenethyl, benzyhydryl, trityl, andthe like, all of which may be optionally.

As used herein, the term “heterocyclic ring” or “heterocyclic ringsystem” is intended to mean a or un member selected from the groupconsisting of stable monocyclic ring having from 5-7 members in the ringitself and having from 1 to 4 hetero ring atoms selected from the groupconsisting of N, O and S; a stable bicyclic ring structure having atotal of from 7 to 12 atoms in the two rings wherein at least one of thetwo rings has from 1 to 4 hetero atoms selected from N, O and S,including bicyclic ring structures wherein any of the described stablemonocyclic heterocyclic rings is fused to a hexane or benzene ring; anda stable tricyclic heterocyclic ring structure having a total of from 10to 16 atoms in the three rings wherein at least one of the three ringshas from 1 to 4 hetero atoms selected from the group consisting of N, Oand S. Any nitrogen and sulfur atoms present in a heterocyclic ring ofsuch a heterocyclic ring structure may be oxidized. Unless indicatedotherwise the terms “heterocyclic ring” or “heterocyclic ring system”include aromatic rings, as well as non-aromatic rings which can besaturated, partially saturated or fully saturated non-aromatic rings.Also, unless indicated otherwise the term “heterocyclic ring system”includes ring structures wherein all of the rings contain at least onehetero atom as well as structures having less than all of the rings inthe ring structure containing at least one hetero atom, for examplebicyclic ring structures wherein one ring is a benzene ring and one ofthe rings has one or more hetero atoms are included within the term“heterocyclic ring systems” as well as bicyclic ring structures whereineach of the two rings has at least one hetero atom. Moreover, the ringstructures described herein may be attached to one or more indicatedpendant groups via any hetero atom or carbon atom which results in astable structure. Further, the term “substituted” means that one or moreof the hydrogen atoms on the ring carbon atom(s) or nitrogen atom(s) ofthe each of the rings in the ring structures described herein may besubstituted by one or more of the indicated substituents if suchreplacement(s) would result in a stable compound. Nitrogen atoms in aring structure may be quaternized, but such compounds are specificallyindicated or are included within the term “a pharmaceutically acceptablesalt” for a particular compound. When the total number of O and S atomsin a single heterocyclic ring is greater than 1, it is preferred thatsuch atoms not be adjacent to one another. Preferably, there are no morethat 1 O or S ring atoms in the same ring of a given heterocyclic ringstructure.

Examples of monocyclic and bicyclic heterocyclic ring systems, inalphabetical order, are acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl,carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl and xanthenyl. Preferred heterocyclic ring structuresinclude, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl,1H-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring andspiro compounds containing, for example, the above heterocyclic ringstructures.

As used herein, the term “aromatic heterocyclic ring system” hasessentially the same definition as for the monocyclic and bicyclic ringsystems except that at least one ring of the ring system is an aromaticheterocyclic ring or the bicyclic ring has an aromatic or non-aromaticheterocyclic ring fused to an aromatic carbocyclic ring structure.

The terms “halo” or “halogen” as used herein refer to Cl, Br, F or Isubstituents. The term “haloalkyl”, and the like, refer to an aliphaticcarbon radicals having at least one hydrogen atom may be optionallysubstituted by a Cl, Br, F or I atom, including mixtures of differenthalo atoms. Trihaloalkyl includes trifluoromethyl and the like aspreferred radicals, for example.

The term “methylene” refers to —CH₂—.

The term “pharmaceutically acceptable salts” includes salts of compoundsderived from the combination of a compound and an organic or inorganicacid. These compounds are useful in both free base and salt form. Inpractice, the use of the salt form amounts to use of the base form; bothacid and base addition salts are within the scope of the presentinvention.

“Pharmaceutically acceptable acid addition salt” refers to saltsretaining the biological effectiveness and properties of the free basesand which are not biologically or otherwise undesirable, formed withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid and the like, and organic acids suchas acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalicacid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaricacid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicyclic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particularly preferred are the ammonium, potassium, sodium,calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases include salts of primary, secondary,and tertiary amines, amines including naturally occurring amines, cyclicamines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, methylglucamine, theobromine,pulines, piperizine, piperidine, N-ethylpiperidine, polyamine resins andthe like. Particularly preferred organic nontoxic bases areisopropylamine, diethylamine, ethanolamine, trimethamine,dicyclohexylamine, choline, and caffeine.

“Biological property” for the purposes herein means an in vivo effectoror antigenic function or activity that is directly or indirectlyperformed by a compound of this invention that are often shown by invitro assays. Effector functions include receptor or ligand binding, anyenzyme activity or enzyme modulatory activity, any carrier bindingactivity, any hormonal activity, any activity in promoting or inhibitingadhesion of cells to an extracellular matrix or cell surface molecules,or any structural role. Antigenic functions include possession of anepitope or antigenic site that is capable of reacting with antibodiesraised against it.

The “therapeutically effective amount” of a compound of the presentinvention will depend on the route of administration, the type ofwarm-blooded animal being treated, and the physical characteristics ofthe specific animal under consideration. These factors and theirrelationship to determining this amount are well known to skilledpractitioners in the medical arts. This amount and the method ofadministration can be tailored to achieve optimal efficacy but willdepend on such factors as weight, diet, concurrent medication and otherfactors which as noted hose skilled in the medical arts will recognize.

The invention relates to nitrogen-containing heterocyclic quinolinecompounds represented by general formula (I):

wherein:

-   V is a member selected from the group consisting of an oxygen atom,    a sulfur atom and ═N—CN;-   W is 1,4-piperazinediyl or 1,4-homopiperazinediyl in which carbons    on the ring may be by 0 to 4 C₁ to C₁₆ alkyl groups which may be the    same or different and each alkyl group my be independently    substitituted by 0-4 R^(a) groups;    -   wherein R^(a) is a member selected from the group consisting of        halo, haloalkyl, —CN, —CN(R^(b), R^(c)),—N(R^(b), R^(c)),        —C(═O)—N(R^(b), R^(c)), —NO₂, —SO₂N(R^(b), R^(c)), —SO₂R^(b),        —(CH₂)_(m)NR^(b)R^(c), —(CH₂)_(m)—C(═NR^(b))—R^(c),        —(CH₂)_(m)—C(═NR^(b))—N(R^(b),R^(c)),        —(CH₂)_(m)—N(R^(b))—C(═NR^(b))—N(R^(b),R^(c)),        —(CH₂)_(m)—NR^(b)—C₃₋₆heterocyclics, —C₁₋₄alkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CF₃,        —OR^(b), and a 5-6 membered heterocyclic system containing from        1-4 heteroatoms selected from N, O and S, wherein from 1-4        hydrogen atoms on the heterocyclic system may be independently        replaced with a member selected from the group consisting of        halo, —CN, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C³⁻⁸cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;        -   wherein            -   m is 0 to 2,            -   R^(b) and R^(c) are each independently a member selected                from the group consisting of —H, —OR^(d), —N(—R^(d),                —R^(e)), —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,                —C₃₋₈cycloalkyl, -CO₄alkylC₃₋₈cycloalkyl,                —C₀₋₄alkylphenyl and —C₀₋₄alkylnaphthyl, wherein from                1-4 hydrogen atoms on the ring atoms of the phenyl and                naphthyl moieties may be independently replaced with a                member selected from the group consisting of halo,                —C₁₋₄alkyl, —C₂₋₆alkenyl,            -   —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl,                —CN, and —NO₂, and R^(d) and R^(e) are each                independently a member selected from the group                consisting of —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,                —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl;            -   or R^(b) and R^(c) taken together with a carbon atom or                nitrogen atom to which they are attached can form a 3-8                membered cycloalkyl or a heterocyclic ring system,                wherein the heterocyclic ring system may optionally have                from 3 to 10 ring atoms, with 1 to 2 rings being in the                ring system and contain from 1-4 heteroatoms selected                from N, O and S, wherein from 1-4 hydrogen atoms on the                heterocyclic ring system may be independently replaced                with a member selected from the group consisting of                halo, haloalkyl, —CN, —CN(R^(b), R^(c)),—N(R^(b),                R^(c)), —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,                —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;-   X is a member selected from the group consisting of:-   H, T—Z, F and Cl; wherein Z is OH, CN or CHO; T is C₁₋₁₆ alkylidene    chain optionally interrupted by O , S, —C(═O)O, —OC(═O)—, —C═O;-   R¹ is a member selected from the group consisting of:-   a hydrogen atom, a C₁ to C₁₆ alkyl group which may be optionally    substituted by 0 to 4 R^(1a) groups, a C₂ to C₁₆ alkenyl group which    may be optionally substituted by 0 to 4 R^(1a) groups, a C₂ to C₁₆    cycloalkyl group which may be optionally substituted by 0 to 4    R^(1a) groups, a partially or fully saturated monocyclic or bicyclic    heterocyclic ring system having 5 to 10 ring atoms and 1 to 4 of the    ring atoms is a member selected from the group consisting of O, S,    and N, wherein the heterocylic ring system is by 0 to 4 R^(1a)    groups, a heteroaryl ring system having 5 to 10 ring atoms and 1 to    4 of the ring atoms is a member selected from the group consisting    of O, S, and N, wherein the heterocylic ring system may be    optionally substituted by 0 to 4 R^(1a) groups, and a    heteroarylalkyl group having from 5 to 10 ring atoms and 1 to 16    carbon atoms in the alkyl portion, and 1 to 4 of the ring atoms is a    member selected from the group consisting of O, S, and N, wherein    the heteroaryl ring may be optionally substituted by 0 to 4 R^(1a)    groups, wherein R^(1a) is a member selected from the group    consisting of halo, haloalkyl, —CN, —CN(R^(b), R^(c)),—N(R^(b),    R^(c)), —C(═O)—N(R^(1b), R^(1c)), —NO₂, —SO₂N(R^(1b), R^(1c)),    —SO₂R^(1b), —(CH₂)_(n)NR^(1b)R^(1c), —(CH₂)_(n)—C(═NR^(1b))—R^(1c),    —(CH₂)_(n)—C(═NR^(1b))—N(R^(1b),R^(1c)),    —(CH₂)_(n)—N(R^(1b))—C(═NR^(1b))—N(R^(1b),R^(1c)),    —(CH₂)_(n)—NR^(1b)—C₃₋₆heterocyclics, —C₁₋₄alkyl, —C₂₋₆alkenyl,    —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CF₃,    —OR^(1b), and a 5-6 membered heterocyclic system containing from 1-4    heteroatoms selected from N, O and S, wherein from 1-4 hydrogen    atoms on the heterocyclic system may be independently replaced with    a member selected from the group consisting of halo, haloalkyl, —CN,    —CN(R^(b), R^(c)),—N(R^(b), R^(c)), —C¹⁻⁴alkyl, —C₂₋₆alkenyl,    —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃gcycloalkyl and —NO₂;    -   wherein        -   n is 0 to 2,        -   R^(1b) and R^(1c) are each independently a member selected            from the group consisting of —H, —OR^(1d), —N(—R^(1d),            —R^(1e)), —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,            —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl            and —C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on            the ring atoms of the phenyl and naphthyl moieties may be            independently replaced with a member selected from the group            consisting of halo, haloalkyl, —C₁₋₄alkyl, —C₂₋₆alkenyl,            —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl,            —CN, and —NO₂, and R^(1d) and R^(1e) are each independently            a member selected from the group consisting of —C₁₋₄alkyl,            —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,            —C₀₋₄alkylC₃₋₈cycloalkyl;        -   or R^(b) and R^(c) taken together with a carbon atom or            nitrogen atom to which they are attached can form a 3-8            membered cycloalkyl or a heterocyclic ring system, wherein            the heterocyclic ring system may optionally have from 3 to            10 ring atoms, with 1 to 2 rings being in the ring system            and contain from 1-4 heteroatoms selected from N, O and S,            wherein from 1-4 hydrogen atoms on the heterocyclic ring            system may be independently replaced with a member selected            from the group consisting of halo, haloalkyl, —CN,            —CN(R^(b), R^(c)),—N(R^(b), R^(c)), —C₁₋₄alkyl,            —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,            —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;-   R² is a member selected from the group consisting of:    -   (g) a hydrogen atom, a C₁ to C₁₆ alkyl group which may be        optionally substituted by 0 to 4 R^(2a) groups; a C₂ to C₁₆        alkenyl group which may be optionally substituted by 0 to 4        R^(2a) groups, a C₂ to C₁₆ cycloalkyl group which may be        optionally substituted by 0 to 4 R^(2a) groups, wherein R^(2a)        is a member selected rom the group consisting of halo,        haloalkyl, —CN, —CN(R^(b), R^(c)),—N(R^(b), R^(c)),        —C(═O)—N(R^(2b), R^(2c)), —NO₂, —SO₂N(R^(2b), R^(2c)),        —SO₂R^(2b), —(CH₂)_(p)NR^(2b)R^(2c),        —(CH₂)_(p)—C(═NR^(2b))—R^(2c),        —(CH₂)_(p)—C(═NR^(2b))—N(R^(2b),R^(2c)),        —(CH₂)_(p)—N(R^(2b))—C(═NR^(2b))—N(R^(2b),R^(2c)),        —(CH₂)_(p)—NR^(2b)—C₃₋₆heterocyclics, —C₁₋₄alkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CF₃,        —OR^(1b), and a 5-6 membered heterocyclic system containing from        1-4 heteroatoms selected from N, O and S, wherein from 1-4        hydrogen atoms on the heterocyclic system may be independently        replaced with a member selected from the group consisting of        halo, haloalkyl, —CN, —CN(R^(b), R^(c)),—N(R^(b), R^(c)),        —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;        -   wherein            -   p is 0 to 2,            -   R^(2b) and R^(2c) are each independently a member                selected from the group consisting of —H, —OR^(2d),                —N(—R^(2d), —R^(2e)), —C₁₋₄alkyl, —C₂₋₆alkenyl,                —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl,                —C₀₋₄alkylphenyl and —C₀₋₄alkylnaphthyl, wherein from                1-4 hydrogen atoms on the ring atoms of the phenyl and                naphthyl moieties may be independently replaced with a                member selected from the group consisting of halo,                haloalkyl, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,                —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and                —NO₂, and R^(2d) and R^(2e) are each independently a                member selected from the group consisting of —C₁₋₄alkyl,                —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,                —C₀₋₄alkylC₃₋₈cycloalkyl;            -   or R^(2b) and R^(2c) taken together with a carbon atom                or nitrogen atom to which they are attached can form a                3-8 membered cycloalkyl or a heterocyclic ring system,                wherein the heterocyclic ring system may optionally have                from 3 to 10 ring atoms, with 1 to 2 rings being in the                ring system and contain from 1-4 heteroatoms selected                from N, O and S, wherein from 1-4 hydrogen atoms on the                heterocyclic ring system may be independently replaced                with a member selected from the group consisting of                halo, haloalkyl, —CN, —CN(R^(b), R^(c)),—N(R^(b),                R^(c)),—C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,                —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;    -   (h) phenyl, which is independently substituted with 0-2 R^(2a)        substituents as defined above;    -   (i) naphthyl, which is independently substituted with 0-2 R^(2a)        substituents as defined above; and    -   (j) a monocyclic or fused bicyclic heterocyclic ring system        having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the        ring system are selected from N, O and S, and wherein the ring        system may be optionally substituted with 0-2 R^(2a)        substituents as defined above;    -   (k) —C(═O)—R¹⁰, wherein R¹⁰ is independently a member defined        the same as R¹ above;    -   (l) —S(═O)₁₋₂—R¹¹, wherein R¹¹ is independently a member defined        the same as R¹ above, except that R¹¹ is other than hydrogen;-   R³, R⁴, R⁵ and R⁶ are each independently a member selected from the    group consisting of:    -   (a) a hydrogen atom, a halogen atom, an optionally substituted        alkyl group, a nitro group, a cyano group,    -   (b) —O—R¹², wherein R¹² is independently a member selected from        the group as defined above for R¹⁰;    -   (c) —C(═O)—R¹³, wherein R¹³ is independently a member selected        from the group as defined above for R¹⁰;    -   (d) —SO₂R¹⁴, wherein R¹⁴ is independently a member selected from        the group as defined above for R¹⁰;    -   (e) —N(—R¹⁵, —R¹⁶), wherein each of R¹⁵ and R¹⁶ are        independently a member selected from the group as defined above        for R¹⁰, or R¹⁵ and R¹⁶ are combined together with the adjoining        nitrogen atom to represent an optionally substituted        nitrogen-containing heterocyclic ring system having from 5 to 10        ring atoms, wherein 1-4 ring atoms of the ring system are        selected from N, O and S, and wherein the ring system may be        optionally substituted with 0-2 substituents as defined above        for R^(2a);    -   (f) —SO₂R¹⁷, wherein R¹⁷ is independently a member selected from        the group as defined above for R¹⁰;    -   (g) a radical of the formula:    -   wherein        -   X¹ represents an oxygen atom or a sulfur atom;        -   R¹⁸ is a member selected from the group consisting of            -   (a) a member selected independently from the group as                defined above for R¹⁰;            -   (b) —O—R¹⁹, wherein R¹⁹ is a member selected                independently from the group as defined above for R₁₀;                or            -   (c) —N(—R²⁰, —R²¹), wherein each of R²⁰ and R²¹ is                independently a member selected independently from the                group as defined above for R¹⁰, or R²⁰ and R²¹ are                combined together with the adjoining nitrogen atom to                represent an optionally substituted nitrogen-containing                heterocyclic ring system having from 5 to 10 ring atoms,                wherein 1-4 ring atoms of the ring system are selected                from N, O and S, and wherein the ring system may be                optionally substituted with 0-2 substituents as defined                above for R^(2a);    -   (h) a radical of the formula:    -   wherein z is an integer from 0 to 2;        -   when z is 0,            -   R²² is a member selected independently from the group as                defined above for R¹⁰;        -   when z is 1,            -   R²² is a member selected independently from the group as                defined above for R¹¹;        -   when z is 2,            -   R²² is a member selected from the group consisting of:            -   (e) a member selected independently from the group as                defined above for R¹¹;            -   (f) —O—R²³, wherein R²³ is a a member selected                independently from the group as defined above for R¹⁰;            -   (g) —N(—R²⁴, R²⁵), wherein R²⁴ and R²⁵ are each                independently a member selected independently from the                group as defined above for R¹⁰, or R²⁴ and R²⁴ are                combined together with the adjoining nitrogen atom to                represent an optionally substituted nitrogen-containing                heterocyclic ring system having from 5 to 10 ring atoms,                wherein 1-4 ring atoms of the ring system are selected                from N, O and S, and wherein the ring system may be                optionally substituted with 0-2 substituents as defined                above for R^(2a);            -   (h) —C(═O)—R²⁶, wherein R²⁶ is a member selected                independently from the group as defined above for R¹⁰,                or R²⁶ is the group —O—R²⁷, wherein R²⁷ is a member                selected independently from the group as defined above                for R¹⁰, or R²⁷ is the group —N(—R²⁸, —R²⁹), wherein R²⁸                and R²⁹ are each independently a member selected                independently from the group as defined above for R¹⁰                or, or R²⁸ and R²⁹ are combined together with the                adjoining nitrogen atom to represent an optionally                substituted nitrogen-containing heterocyclic ring system                having from 5 to 10 ring atoms, wherein 1-4 ring atoms                of the ring system are selected from N, O and S, and                wherein the ring system may be optionally substituted                with 0-2 substituents as defined above for R^(2a); and                wherein any two of R³, R⁴, R⁵ and R⁶ attached to                adjoining carbons taken together with the carbon atom to                which they are attached form a ring structure which is a                member selected from the following:    -   (d) a 5 to 6 membered saturated heterocyclic ring having two        oxygen ring atoms interrupted by one or two carbons,        respectively;    -   (e) an optionally substituted phenyl group; and    -   (f) a heterocyclic ring which is a member selected from the        following group:        -   wherein:        -   A is an oxygen atom or a sulfur atom;        -   Q¹ is a member selected from the group consisting of:            -   (a) the group as defined above for R¹⁰; or            -   (b) —N(—R³¹ , —R³²), wherein R³¹ and R³² are each                independently a member selected independently from the                group as defined above for R¹⁰;            -   —O—R³³ or —S—R³³, wherein R³³ is a member selected                independently from the group as defined above for R¹⁰;        -   Q² is a member selected from the group consisting of ═O, ═S,            ═N—CN; and        -   R³⁰, R³⁴, R³⁵ and R³⁶ are each independently a member            selected from the group as defined above for R¹⁰; and    -   and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

Another embodiment of the invention provides nitrogen-containingheterocyclic quinoline compounds represented by general formula (I):

wherein:

-   V is a member selected from the group consisting of an oxygen atom,    a sulfur atom and ═N—CN;-   W is 1,4-piperazinediyl or 1,4-homopiperazinediyl;-   X is a member selected from the group consisting of:-   (—CH₂)₀₋₈—CH₂—OH, (—CH₂)₁₋₈—C(═O)—O(—CH₂)₀₋₈—CH₃, (—CH₂)₁₋₈—C(═O)—H,    (—CH₂)₀₋₈—CN, F and Cl;-   R¹ is a member selected from the group consisting of:-   a hydrogen atom, a C₁ to C₁₆ alkyl group which may be optionally    substituted by 0 to 4 R^(1a) groups, a C₂ to C₁₆ alkenyl group which    may be optionally substituted by 0 to 4 R^(1a) groups, a C₂ to C₁₆    cycloalkyl group which may be optionally substituted by 0 to 4    R^(1a) groups, a partially or fully saturated monocyclic or bicyclic    heterocyclic ring system having 5 to 10 ring atoms and 1 to 4 of the    ring atoms is a member selected from the group consisting of O, S,    and N, wherein the heterocylic ring system may be optionally    substituted by 0 to 4 R^(1a) groups, a heteroaryl ring system having    5 to 10 ring atoms and 1 to 4 of the ring atoms is a member selected    from the group consisting of O, S, and N, wherein the heterocylic    ring system may be optionally substituted by 0 to 4 R^(1a) groups,    and a heteroarylalkyl group having from 5 to 10 ring atoms and 1 to    16 carbon atoms in the alkyl portion, and 1 to 4 of the ring atoms    is a member selected from the group consisting of O, S, and N,    wherein the heteroaryl ring may be optionally substituted by 0 to 4    R^(1a) groups, wherein R^(1a) is a member selected from the group    consisting of halo, haloalkyl, —CN, —CN(R^(b), R^(c)),—N(R^(b),    R^(c)), —C(═O)—N(R^(1b), R^(1c)), —NO₂, —SO₂N(R^(1b), R^(1c)),    —SO₂R^(1b), —(CH₂)_(n)NR^(1b)R^(1c), —(CH₂)_(n)—C(═NR^(1b))—R^(1c),    —(CH₂)_(n)—C(═NR^(1b))—N(R^(1b),R^(1c)),    —(CH₂)_(n)—N(R^(1b))—C(═NR^(1b))—N(R^(1b),R^(1c)),    —(CH₂)_(n)—NR^(1b)—C₃₋₆heterocyclics, —C₁₋₄alkyl, —C₂₋₆alkenyl,    —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CF₃,    —OR^(1b), and a 5-6 membered heterocyclic system containing from 1-4    heteroatoms selected from N, O and S, wherein from 1-4 hydrogen    atoms on the heterocyclic system may be independently replaced with    a member selected from the group consisting of halo, haloalkyl, —CN,    —CN(R^(b), R^(c)),—N(R^(b), R^(c)), —C₁₋₄alkyl, —C₂₋₆alkenyl,    —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;    -   wherein        -   n is 0 to 2,        -   R^(1b) and R^(1c) are each independently a member selected            from the group consisting of —H, —OR^(1d), —N(—R^(1d),            R^(1e)), —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,            —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl            and —C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on            the ring atoms of the phenyl and naphthyl moieties may be            independently replaced with a member selected from the group            consisting of halo, haloalkyl, —C₁₋₄alkyl, —C₂₋₆alkenyl,            —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl,            —CN, and —NO₂, and R^(1d) and R^(1e) are each independently            a member selected from the group consisting of —C₁₋₄alkyl,            —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,            —C₀₋₄alkylC₃₋₈cycloalkyl;        -   or R^(b) and R^(c) taken together with a carbon atom or            nitrogen atom to which they are attached can form a 3-8            membered cycloalkyl or a heterocyclic ring system, wherein            the heterocyclic ring system may optionally have from 3 to            10 ring atoms, with 1 to 2 rings being in the ring system            and contain from 1-4 heteroatoms selected from N, O and S,            wherein from 1-4 hydrogen atoms on the heterocyclic ring            system may be independently replaced with a member selected            from the group consisting of halo, haloalkyl, —CN,            —CN(R^(b), R^(c)),—N(R^(b), R^(c)), —C₁₋₄alkyl,            —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,            —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;-   R² is a member selected from the group consisting of:    -   (g) a hydrogen atom, a C₁ to C₁₆ alkyl group which may be        optionally substituted by 0 to 4 R^(2a) groups, a C₂ to C₁₆        alkenyl group which may be optionally substituted by 0 to 4        R^(2a) groups, a C₂ to C₁₆ cycloalkyl group which may be        optionally substituted by 0 to 4 R^(2a) groups, wherein R², is a        member selected rom the group consisting of halo, haloalkyl,        —CN, —CN(R^(b), R^(c)),—N(R^(b), R^(c)), —C(═O)—N(R^(2b),        R^(2c)), —NO₂, —SO₂N(R^(2b), R^(2c)), —SO₂R^(2b),        —(CH₂)_(p)NR^(2b)R^(2c), —(CH₂)_(p)—C(═NR^(2b))—R^(2c),        —(CH₂)_(p)—C(═NR^(2b))—N(R^(2b),R^(2c)),        —(CH₂)_(p)—N(R^(2b))—C(═NR^(2b))—N(R^(2b),R^(2c)),        —(CH₂)_(p)—NR^(2b)—C₃₋₆heterocyclics, —C₁ ₋₄alkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CF₃,        —OR^(1b), and a 5-6 membered heterocyclic system containing from        1-4 heteroatoms selected from N, O and S, wherein from 1-4        hydrogen atoms on the heterocyclic system may be independently        replaced with a member selected from the group consisting of        halo, haloalkyl, —CN, —CN(R^(b), R^(c)),—N(R^(b), R^(c)),        —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;        -   wherein            -   p is 0 to 2,            -   R^(2b) and R^(2c) are each independently a member                selected from the group consisting of —H, —OR^(2d),                —N(—R^(2d), R^(2e)), C₁₋₄alkyl, —C₂₋₆alkenyl,                —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, -C₀₋₄alkylC₃₋₈cycloalkyl,                —C₀₋₄alkylphenyl and —C₀₋₄alkylnaphthyl, wherein from                1-4 hydrogen atoms on the ring atoms of the phenyl and                naphthyl moieties may be independently replaced with a                member selected from the group consisting of halo,                haloalkyl, —C₁₋₄alkyl,            -   —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,                —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂, and R^(2d) and                R^(2e) are each independently a member selected from the                group consisting of —C₁₋₄alkyl, —C₂₋₆alkenyl,                —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl;            -   or R^(2b) and R^(2c) taken together with a carbon atom                or nitrogen atom to which they are attached can form a                3-8 membered cycloalkyl or a heterocyclic ring system,                wherein the heterocyclic ring system may optionally have                from 3 to 10 ring atoms, with 1 to 2 rings being in the                ring system and contain from 1-4 heteroatoms selected                from N, O and S, wherein from 1-4 hydrogen atoms on the                heterocyclic ring system may be independently replaced                with a member selected from the group consisting of                halo, haloalkyl, —CN, —CN(R^(b), R^(c)),—N(R^(b),                R^(c)), —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,                —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;    -   (h) phenyl, which is independently substituted with 0-2 R^(2a)        substituents as defined above;    -   (i) naphthyl, which is independently substituted with 0-2 R^(2a)        substituents as defined above; and    -   a monocyclic or fused bicyclic heterocyclic ring system having        from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring        system are selected from N, O and S, and wherein the ring system        may be optionally substituted with 0-2 R^(2a) substituents as        defined above;    -   (k) —C(═O)—R¹⁰, wherein R¹⁰ is independently a member defined        the same as R¹ above;    -   (l) —S(═O)₁₋₂—R¹¹, wherein R¹¹ is independently a member defined        the same as R¹ above, except that R¹¹ is other than hydrogen;-   R³, R⁴, R⁵ and R⁶ are each independently a member selected from the    group consisting of:    -   (a) a hydrogen atom, a halogen atom, an optionally substituted        alkyl group, a nitro group, a cyano group, and    -   (b) —O—R¹², wherein R¹² is independently a member selected from        the group as defined above for R¹⁰;    -   and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

Another embodiment of the invention provides nitrogen-containingheterocyclic quinoline compounds represented by general formula (I):(—CH₂)₀₋₁—CH₂—OH, (—CH₂)₁₋₂—C(═O)—O(—CH₂)₀₋₈—CH₃, (—CH₂)₁₋₂—C(═O)—H,(—CH₂)₀₋₁—CN, F and Cl;

In a preferred embodiment, the present invention provides compound asdescribed above for formula I, represented by formula Ia as follows:

wherein

-   V is a member selected from the group consisting of an oxygen atom,    a sulfur atom and ═N—CN-   X is a member selected from the group consisting of:-   —(CH₂)₁₋₂—OH, —CH₂—C(═O)—O(—CH₂)₀₋₈—CH₃, —CH₂—C(═O)—H, and    (—CH₂)₀₋₁—CN, F, Cl;-   Y is a member selected from the group consisting of:-   —CN, —Br, —CF₃, —O—C₁₋₈ alkyl that is independently straight or    branched chained, —O-phenyl, —O-naphthyl, —O-indolyl and    —O-isoquinolinyl;-   R² and R⁴ are each independently a member selected from the group    consisting of:-   —O—CH₃, —O(—CH₂)—CH₃, —O—CH₂—CH═CH₂, —O—CH₂—C≡CH and    —O(—CH₂)₂₋₃—R^(2a);-   R^(2a) is a member selected from the group consisting of:-   —OH, —O—CH₃, —O—CH₂—CH₃, —NH₂, —N(—CH₃)₂, —NH(—CH₂-phenyl),    —NH(-Phenyl), —CN,    -   and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

In another embodiment, the present invention provides compound asdescribed above for formula I, represented by formula Ia as follows:

wherein

-   V is a member selected from the group consisting of an oxygen atom    and a sulfur atom;-   X is a member selected from the group consisting of:-   —CN, CO₂Et, CHO, CH₂OH, F, and Cl;-   Y is a member selected from the group consisting of:-   —CN, —O—C₁₋₈ alkyl that is independently straight or branched    chained, —O-phenyl, —O-naphthyl, —O-indolyl and —O-isoquinolinyl;-   R² and R⁴ are each different and independently a member selected    from the group consisting of:-   —O—(CH₂—)₀₋₁—CH₃ and —O(—CH₂)₂₋₃—R^(2a);-   R^(2a) is a member selected from the group consisting of:    -   and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

Another embodiment of the invention relates to pharmaceuticallyacceptable salts of the compounds according to formula (I) includepharmaceutically acceptable acid addition salts, metal salts, ammoniumsalts, organic amine addition salts, amino acid addition salts, etc.

Examples of the pharmaceutically acceptable acid addition salts of thecompounds of formula (I) are inorganic acid addition salts such ashydrochloride, sulfate and phosphate, and organic acid addition saltssuch as acetate, maleate, fumarate, tartrate, citrate andmethanesulfonate.

Examples of the pharmaceutically acceptable metal salts are alkali metalsalts such as sodium salt and potassium salt, alkaline earth metal saltssuch as magnesium salt and calcium salt, aluminum salt and zinc salt.Examples of the pharmaceutically acceptable ammonium salts are ammoniumsalt and tetramethyl ammonium salt. Examples of the pharmaceuticallyacceptable organic amine addition salts include heterocyclic amine saltssuch as morpholine and piperidine salts. Examples of thepharmaceutically acceptable amino acid addition salts are salts withlysine, glycine and phenylalanine.

In a preferred embodiment the invention provides compounds according toformula II(a) and formula II(b) as follows:

wherein:

-   V is an oxygen atom, a sulfur atom and ═N—CN;-   Y is a member selected from the group consisting of:    -   —CN, —Br, —CF₃, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl,        —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy,        4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy;    -   and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

In another preferred embodiment the invention provides compoundsaccording to formula (IIc) and formula (IId) as follows:

wherein

-   V is an oxygen atom or a sulfur atom; and-   Y is a member selected from the group consisting of:    -   —CN, —Br, —CF₃, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl,        —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy,        4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy;    -   and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

In still another preferred embodiment the invention provides compoundsaccording to formula II(e) and formula II(f) as follows:

wherein

-   V is an oxygen atom or a sulfur atom; and-   Y is a member selected from the group consisting of:    -   —CN, —Br, —CF₃, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl,        —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy,        4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy;    -   and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

In yet another preferred embodiment the invention provides compoundsaccording to formula II(g) and formula II(h) as follows:

wherein

-   V is an oxygen atom or a sulfur atom;-   Y is a member selected from the group consisting of:    -   —CN, —Br, —CF₃, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl,        —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy,        4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy;-   R^(2a) is a member selected from the group consisting of:    -   —OH, —O—CH₃, —O—CH₂—CH₃, —NH₂, —N(—CH₃)₂, —NH(—CH₂-phenyl),        —NH(-Phenyl), —CN,        and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

The pharmaceutically acceptable salts of the compounds according to theabove formulae include pharmaceutically acceptable acid addition salts,metal salts, ammonium salts, organic amine addition salts, amino acidaddition salts, etc.

The present invention is not limited by the above listed compounds.Analogs of the bicyclic compounds are contemplated.

Further, an especially preferred embodiment of the present inventionprovides a compound as described above, which is selected from the groupconsisting of:N-(4-indol-5-yloxyphenyl){4-[3-cyano-6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl]piperazinyl}carboxamide

N-(4-indol-4-yloxyphenyl){4-[3-cyano-6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl]piperazinyl}carboxamide

{4-[3-cyano-6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}-N-(4-naphthyloxyphenyl)carboxamide

{4-[3-cyano-6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl]piperazinyl}-N-(4-(2-naphthyloxy)phenyl)carboxamide

N-(4-(5-isoquinolyloxy)phenyl){4-[3-cyano-6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl]piperazinyl}carboxamide

{4-[3-cyano-6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl]piperazinyl}-N-(4-phenoxyphenyl)carboxamide

{4-[3-cyano-6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl){4-[3-cyano-6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl]piperazinyl}carboxamide

{4-[3-cyano-6-methoxyl)quinolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl){4-[3-cyano-6-methoxy-7-(2-piperidylethoxy)quinolin-4-yl]piperazinyl}carboxamide

{4-[3-cyano-6-methoxy-7-(3-piperidylpropoxy)quinolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

{4-[3-cyano-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl){4-[3-cyano-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]piperazinyl}carboxamide

{4-[3-cyano-6-methoxy-7-(3-pyrrolidinylpropoxy)quinolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl){4-[3-cyano-6-methoxy-7-(2-(1,2,3,4-tetraazol-2-yl)ethoxy)quinolin-4-yl]piperazinyl}carboxamide

N-(4-cyanophenyl){4-[3-cyano-6-methoxy-7-(2-(1,2,3,4-tetraazolyl)ethoxy)quinolin-4-yl]piperazinyl}carboxamide

{4-[3-cyano-6-methoxy-7-(2-(1,2,3,4-tetraazolyl)ethoxy)quinolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

{4-[3-cyano-6-methoxy-7-(2-(1,2,3,4-tetraazol-2-yl)ethoxy)quinolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

(4-{3-cyano-7-[3-(4,4-difluoropiperidyl)propoxy]-6-methoxyquinolin-4-yl}piperazinyl)-N-[4-(methylethoxy)phenyl]carboxamide

{4-[3-cyano-6-methoxy-7-(3-piperazinylpropoxy)quinolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl)(4-{3-cyano-6-methoxy-7-[3-(4-methylpiperazinyl)propoxy]quinolin-4-yl}piperazinyl)carboxamide

N-(4-cyanophenyl){4-[3-cyano-6-methoxy-7-(3-(1,4-thiazaperhydroin-4-yl)propoxy)quinolin-4-yl]piperazinyl}carboxamide

(4-{3-cyano-7-[3-(1,1-dioxo(1,4-thiazaperhydroin-4-yl))propoxy]-6-methoxyquinolin-4-yl}piperazinyl)—N-(4-cyanophenyl)carboxamide

N-(4-cyanophenyl)[4-(3-cyano-7-ethoxy-6-methoxyquinolin-4-yl)piperazinyl]carboxamide

[4-(3-cyano-7-ethoxy-6-methoxyquinolin-4-yl)piperazinyl]-N-[4-(methylethoxy)phenyl]carboxamide

[4-(3-cyano-7-ethoxy-6-methoxyquinolin-4-yl)piperazinyl]-N-(4-naphthyloxyphenyl)carboxamide

[4-(3-cyano-7-ethoxy-6-methoxyquinolin-4-yl)piperazinyl]-N-(4-indol-4-yloxyphenyl)carboxamide

[4-3-cyano-(7-ethoxy-6-methoxyquinolin-4-yl)piperazinyl]-N-(4-phenoxyphenyl)carboxamide

N-(4-cyanophenyl)[4-(3-cyano-6-methoxy-7-prop-2-enyloxyquinolin-4-yl)piperazinyl]carboxamide

[4-(3-cyano-6-methoxy-7-prop-2-enyloxyquinolin-4-yl)piperazinyl]-N-[4-(methylethoxy)phenyl]carboxamide

[4-(3-cyano-6-methoxy-7-prop-2-enyloxyquinolin-4-yl)piperazinyl]-N-(4-naphthyloxyphenyl)carboxamide

N-(4-indol-4-yloxyphenyl)[4-(3-cyano-6-methoxy-7-prop-2-enyloxyquinolin-4-yl)piperazinyl]carboxamide

[4-(3-cyano-6-methoxy-7-prop-2-enyloxyquinolin-4-yl)piperazinyl]-N-(4-phenoxyphenyl)carboxamide

N-(4-cyanophenyl)[4-(3-cyano-6-methoxy-7-prop-2-ynyloxyquinolin-4-yl)piperazinyl]carboxamide

[4-(3-cyano-6-methoxy-7-prop-2-ynyloxyquinolin-4-yl)piperazinyl]-N-[4-(methylethoxy)phenyl]carboxamide

[4-(3-cyano-6-methoxy-7-prop-2-ynyloxyquinolin-4-yl)piperazinyl]-N-(4-naphthyloxyphenyl)carboxamide

N-(4idol-4yloxyphenyl)[4-(3-cyano-6-methoxy-7-prop-2-ynyloxyquinolin-4-yl)piperazinyl]carboxamide

[4-(3-cyano-6-methoxy-7-prop-2-ynyloxyquinolin-4-yl)piperazinyl]-N-(4-phenoxyphenyl)carboxamide

ethyl-6-methoxy-4-(4-{N-[4-(methylethoxy)phenyl]carbamoyl}piperazinyl)-7-(3-piperidylpropoxy)quinoline-3-carboxylate

ethyl6-methoxy-4-(4-{N-[4-(methylethoxy)phenyl]carbamoyl}piperazinyl)-7-(3-morpholin-4-ylpropoxy)quinoline-3-carboxylate

ethyl6-methoxy-4-(4-{N-[4-(methylethoxy)phenyl]carbamoyl}piperazinyl)-7-(3-(1,2,3-triazolyl)propoxy)quinoline-3-carboxylate

6-methoxy-4-(4-(N-[4-(methylethoxy)phenyl]carbamoyl)piperazinyl)-7-(3-(1,2,3-triazol-2-yl)propoxy)quinoline-3-carboxylicAcid

ethyl4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-(3-piperidylpropoxy)quinoline-3-carboxylate

ethyl4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinoline-3-carboxylate

ethyl4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl)-6-methoxy-7-(3-pyrrolidinylpropoxy)quinoline-3-carboxylate

ethyl4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl)-6-methoxy-7-(3-(1,2,3-triazolyl)propoxy)quinoline-3-carboxylate

ethyl4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-(3-(1,2,3-triazol-2-yl)propoxy)quinoline-3-carboxylate

ethyl4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-(3-(1,2,3,4-tetraazol-2-yl)propoxy)quinoline-3-carboxylate

ethyl4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-(3-(1,2,3,4-tetraazolyl)propoxy)quinoline-3-carboxylate

ethyl7-[3-(1,1-dioxo(1,4-thiazaperhydroin-4-yl))propoxy]-4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxyquinoline-3-carboxylate

ethyl4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-(3-piperazinylpropoxy)quinoline-3-carboxylate

ethyl4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-(2-methoxyethoxy)quinoline-3-carboxylate

ethyl6-methoxy-7-(2-methoxyethoxy)-4-4-{N-[4-(methylethoxy)phenyl]-carbamoyl}piperazinyl)quinoline-3-carboxylate

ethyl4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-[3-(4-methylpiperazinylpropoxy]quinoline-3-carboxylate

{4-[3-carbonyl-6-methoxy-7-(3-piperidylpropoxy)(4-quinolyl)]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

{4-[3-carbonyl-6-methoxy-7-(3-morpholin-4-ylpropoxy)(4-quinolyl)]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

(4-{7-[3-(1,1-dioxo(1,4-thiazaperhydroin-4-yl))propoxy]-3-carbonyl-6-methoxy(4-quinolyl)}piperazinyl)—N-[4-(methylethoxy)phenyl]carboxamide

{4-[3-carbonyl-6-methoxy-7-(3-pyrrolidinylpropoxy)(4-quinolyl)]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

{4-[3-carbonyl-6-methoxy-7-(3-piperidylpropoxy)(4-quinolyl)]piperazinyl}-N-(4-cyanophenyl)carboxamide

{4-[3-carbonyl-6-methoxy-7-(3-morpholin-4-ylpropoxy)(4-quinolyl)]piperazinyl}-N-(4-cyanophenyl)carboxamide

{4-[3-carbonyl-6-methoxy-7-(3-myrpolinylpropoxy)(4-quinoyl)]piperazinyl}-N-(4-cyanophenyl)carboxamide

{4-[3-carbonyl-6-methoxy-7-(3-(1,2,3-trinazolyl)propoxy)(4-quinolyl)]piperazinyl}-N-(4-cyanophenyl)carboxamide

{4-[3-carbonyl-6-methoxy-7-(3-(1,2,3-triazol-2-yl)propoxy)(4-quinolyl)]piperazinyl}-N-(4-cyanophenyl)carboxamide

N-(4-cyanophenyl){4-[3-(hydroxymethyl)-6-methoxy-7-(3-piperidylpropoxy)(4-quinolyl)]piperazinyl}carboxamide

N-(4-cyanophenyl){4-[3-(hydroxymethyl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)(4-quinolyl)]piperazinyl}carboxamide

N-(4-cyanophenyl){4-[3-(hydroxymethyl)-6-methoxy-7-(3-pyrrolidinylpropoxy)(4-quinolyl)]piperazinyl}carboxamide

{4-[3-(hydroxymethyl)-6-methoxy-7-(3-piperidylpropoxy)(4-quinolyl)]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

{4-[3-(hydroxymethyl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)(4-quinolyl)]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

(4-{7-[3-(1,1-dioxo(1,4-thiazaperhydroin-4-yl))propoxy]-3-(hydroxymethyl)-6-methoxy(4-quinolyl)}piperazinyl)-N-[4-(methylethoxy)phenyl]carboxamide

{4-[3-(hydroxymethyl)-6-methoxy-7-(3-pyrrolidinylpropoxy)(4-quinolyl)]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

4-[3-Aminomethyl-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicAcid (4-cyano-phenyl)-amide

4-[3-Aminomethyl-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicAcid(4-isopropoxy-phenyl)-amide

4-[3-Aminomethyl-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicAcid(4-cyano-phenyl)-amide

4-[3-Aminomethyl-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicAcid (4-isopropoxy-phenyl)-amide

4-[3-Cyano-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicAcid (4-cyano-phenyl)-amide

4-[3-Cyano-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylic Acid(4-bromo-phenyl)-amide

4-[3-Cyano-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicAcid (4-isopropoxy-phenyl)-amide

4-({4-[3-Cyano-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carbonyl)}-amino)-benzoicAcid Methyl Ester

4-((4-[3-Cyano-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carbonyl)-amino)-benzoicAcid Methyl Ester

4-[3-Cyano-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicAcid (4-bromo-phenyl)-amide

4-[3-Cyano-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quilolin-4-yl]-piperazine-1-carboxylicAcid (4-trifluoromethyl-phenyl)-amide

4-[3-Cyano-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicAcid (4-fluoro-phenyl)-amide

4-[3-Fluoro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicAcid (4-cyano-phenyl)-amide

4-[3-Fluoro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicAcid (4-isopropoxy-phenyl)-amide

4-[3-Fluoro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicAcid (4-cyano-phenyl)-amide

4-[3-Fluoro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid (4-isopropoxy-phenyl)-amide

4-[3-Fluoro-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicAcid (4-cyano-phenyl)-amide

4-[3-Fluoro-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicAcid (4-bromo-phenyl)-amide

4-[3-Fluoro-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicAcid (4-isopropoxy-phenyl)-amide

4-({4-[3-Fluoro-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carbonyl}-amino)-benzoicAcid Methyl Ester

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Preparation of Compounds

The compounds may be prepared using methods and procedures as generallydescribed in WO 98/14431 published Sep. 12, 1998, which is incorporatedherein by reference. Intermediates can also be made using methods andprocedures described in U.S. Pat. No. 6,002,008; Bioorg. & Med. Chem.Lett., 10: 2825-2828 (2000); WO 0068201; Bioorg. & Med. Chem. Lett., 10:2477-2485, and in J. Med. Chem. ,43: 3244-3256 (2000). Startingmaterials may be made or obtained as described therein as well. Leavinggroups such as halogen, lower alkoxy, lower alkylthio, loweralkylsulfonyloxy, arylsulfonyloxy, etc, may be utilized when necessaryexcept for the reaction point, followed by deprotection. Suitable aminoprotective groups are, for example, those described in T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons Inc. (1981),etc., such as ethoxycarbonyl, t-butoxycarbonyl, acetyl and benzyl. Theprotective groups can be introduced and eliminated according toconventional methods used in organic synthetic chemistry, e.g., T. W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons Inc.(1981).

In such processes, if the defined groups change under the conditions ofthe working method or are not appropriate for carrying out the method,the desired compound can be obtained by using the methods forintroducing and eliminating protective groups which are conventionallyused in organic synthetic chemistry, e.g., T. W. Greene, ProtectiveGroups in Organic Synthesis, John Wiley & Sons Inc. (1981), etc.Conversion of functional groups contained in the substituents can becarried out by known methods, e.g., R. C. Larock, Comprehensive OrganicTransformations (1989) in addition to the above-described processes, andsome of the active compounds of formula I may be utilized asintermediates for further synthesizing novel derivatives according toformula I.

The intermediates and the desired compounds in the processes describedabove can be isolated and purified by purification methodsconventionally used in organic synthetic chemistry, for example,neutralization, filtration, extraction, washing, drying, concentration,recrystallization, and various kinds of chromatography. Theintermediates may be subjected to the subsequent reaction withoutpurification.

There may be tautomers for some formulae set forth as embodiments of theinvention, and the present invention covers all possible isomersincluding tautomers and mixtures thereof. Where chiral carbons lendthemselves to two different enantiomers, both enantiomers arecontemplated as well as procedures for separating the two enantiomers.

In the case where a salt of a compound of the above formulae is desiredand the compound is produced in the form of the desired salt, it can besubjected to purification as such. In the case where a compound offormula I is produced in the free state and its salt is desired, thecompound of formula I is dissolved or suspended in a suitable organicsolvent, followed by addition of an acid or a base to form a salt.

The following non-limiting reaction Schemes I and II illustratepreferred embodiments of the invention with respect to making compoundsaccording to the invention.

This synthesis of atert-butyl-4-[3-cyano-6-methoxy-7-(phenylmethoxy)quinolin-4-yl]-piperazinecarboxylate compound, provides an intermediate that can be utilized inthe synthesis of various compounds (the scheme can be adapted to producebicyclic position isomers) as described above for formula I. The nitrofunctionality is reduced with a reducing agent such as tin chloride,hydrogen in the presence of palladium on carbon, hydrogen in thepresence of raney nickel, and the like, followed by addition of thealkylenenitrile derivative and cyclization to afford quinolinone. Thesynthesis of 3-cyano-4-Cl-quinoline is effected by treating3-cyano-quinolinone with halogenating reagents such as thionyl chloride,oxalyl chloride and phosphorous oxychloride, or phosphorouspentachloride in presence of solvent such as toluene, or carbontetrachloride. This intermediate is obtained by treating3-cyano-4-chloro-quinoline with Boc-piperazine in an appropriatesolvent, such as isopropanol, acetonitrile, or THF at room or refluxtemperature for 1-6 h in presence of base triethylamine or pyridine.

This illustrated Scheme II provides the synthesis of various urea orthio urea intermediates from the intermediate obtained in Scheme I, orby other procedures. The intermediate form Scheme I (or its bicyclicposition isomer) is debenzylated under hydrogenation conditions followedby alkylation with various alkyl halides. Deprotection of Boc group iseffected by trifluoroacetic acid followed by treatment with variousisocyanates or thioisocyanates to afford the final urea or thioureacompounds. In cases where the isocyanates are not commerciallyavailable, the piperazine intermediate may be treated with phosgene togive a carbamoyl chloride intermediate followed by reaction with variousanilines. The piperazine intermediate can also be treated withp-nitrophenyl chloroformate to afford a nitrophenyl carbamateintermediate that can be treated with various anilines to afford thedesired ureas. If the urea compound has a terminal NH₂ group (or one ormore of the hydrogen atoms on this amino group is substituted by adisplaceable substituent), then this compound may be utilized anintermediate compound with which to produce a urea compound terminatedwith a —NH-phenyl-Y groups. Alternatively, if a different Y group isdesired on the phenyl group, a replaceable para position leaving groupphenyl substituent may be displaced after coupling to provide theparticular Y substituent as described for formula Ia, above.

Scheme III illustrates a preferred embodiment for producing the4-halo-3-cyanoquinoline derivatives of step 4 in Scheme I. Theorthoamino ester is treated with dimethylformamide-dimethyl acetal toafford dimethylamidine intermediate. This intermediate is treated at lowtemperature with the anion of acetonitrile to afford the3-cyano-4-quinolinone derivatives. The synthesis of3-cyano-4-chloro-quinoline is effected by treating the3-cyanoquinolinone with halogenating reagents such as thionyl chloride,oxalyl chloride and phosphorous oxychloride, or phosphorouspentachloride in presence of solvent such as toluene, or carbontetrachloride. The piperazine products of Scheme I can be produced fromthe final Scheme III product by repeating step 5 of Scheme I, above.

Scheme IV illustrates the synthesis of atert-butyl-4-[3-Ethylcarboxylate-6-methoxy-7-(phenylmethoxy)quinolin-4-yl]-piperazinecarboxylate andtert-butyl-4-[3-Fluoro-6-methoxy-7-(phenylmethoxy)quinolin-4-yl]-piperazinecarboxylate compounds, provides an intermediate that can be utilized inthe synthesis of various compounds (the scheme can be adapted to producebicyclic position isomers) as described above for formula I. The cyanofunctionality of 3-cyano-4-quinolone is hydrolyzed under basic or acidicconditions to afford 3-carboxylic acid intermediate, which is thenesterified to afford 3-ethylcarboxylate-4-quinolone intermediate. Thesynthesis of 3-ethylcarboxylate-4-Cl-quinoline is effected by treating3-cyano-quinolinone with halogenating reagents such as thionyl chloride,oxalyl chloride and phosphorous oxychloride, or phosphorouspentachloride in presence of solvent such as toluene, or carbontetrachloride. This intermediate is obtained by treating3-ethylcarboxylate-4-chloro-quinoline with Boc-piperazine in anappropriate solvent, such as isopropanol, acetonitrile, or THF at roomor reflux temperature for 1-6h in presence of base triethylamine orpyridine. The 3-fluoro-4-chloroquinoline is synthesized via4-chloro-3-carboxylic acid quinolone by curtius rearrangement withdiphenyphosphorylazide in presence of t-BuOH to afford 3-Boc-aminointermediate. After removal of Boc functionality under acidic condition,amino group is diazotized with sodium nitrate and the added aqueosfluoboric acid to precipitate diazonium terafluoroborate. This washeated to afford the 3-fluoro-4-chloroquinoline intermediate. Theintermediates I and II were converted to various ureas or thioureas asshown in Scheme II. The intermediate form Scheme IV (or its bicyclicposition isomer) is debenzylated under hydrogenation conditions followedby alkylation with various alkyl halides. Deprotection of Boc group iseffected by trifluoroacetic acid followed by treatment with variousisocyanates or thioisocyanates to afford the final urea or thioureacompounds as shown in Scheme II. In cases where the isocyanates are notcommercially available, the piperazine intermediate may be treated withphosgene to give a carbamoyl chloride intermediate followed by reactionwith various anilines. The piperazine intermediate can also be treatedwith p-nitrophenyl chloroformate to afford a nitrophenyl carbamateintermediate that can be treated with various anilines to afford thedesired ureas.

Such procedures for producing the claimed compounds are merely anillustration of a preferred aspect of the invention. Other proceduresand adaptations will be apparent to one of ordinary skill in the artupon views these reaction schemes and the structures of the compoundsaccording to the invention. Such procedures are deemed to be within thescope of the present invention.

Also, the compounds of formula I or Ia and pharmaceutically acceptablesalts thereof may exist in the form of adducts with water (hydrates) orvarious solvents, which are also within the scope of the presentinvention.

The following non-limiting examples are provided to better illustratethe present invention.

EXAMPLE 1

Preparation of{4-[3-cyano-6-methoxy-7-(3-pipetidylpropoxy)quinolin-4-yl)piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

The starting material was prepared as follows:

Step A: Preparation of4-chloro-6-methoxy-7-(3-pipendylpropoxy)quinoline-3-carbonitrile

A solution of ethyl 2-amino-5-methoxy-4-(3-piperidylpropoxy)benzoate(1.0 g, 2.98 mmol) and dimethylformamide dimethylacetal (0.84 mL, 5.95mmol) in 3 mL of DMF was heated at reflux for 3 h. Volatile material wasremoved and the residue was azeotroped twice with toluene and dried invacuo.

To a chilled (−78° C.) solution of 2.50 mL n-BuLi (6.22 mmol) in 2.30 mLTHF was added THF solution (2 mL) of CH3CN (0.341 mL, 6.53 mmol)dropwise under argon. After 20 min at −78° C. added formamidine productfrom step 1 in THF (2.5 mL) dropwise over 10 min. The reaction wasstirred at −78° C. for 1 h and then quenched with 0.81 mL of glacialacetic acid. The mixture was warmed to RT and the solvent evaporated.The residue was purified by reverse phase HPLC to afford 0.425 g of4-hydroxy-6-methoxy-7-(3-piperidylpropoxy)quinoline-3-carbonitrile aswhite solid. MS(ES) 342 (M+H)

A slurry of 4-hydroxyquinoline (0.700 g, 1.45 mmol) in SOCl 2 (5 mL) wastreated with 0.400 mL of DMF. This mixture was heated at 90° C. for 30min during that time all the starting material was consumed by HPLC. Thesolvent was evaporated in vacuo and then azetroped with toluene toremove excess thionyl chloride. The residue was suspended in H2O/CH2Cl2(1:1) to this added 20% K2CO3 at −10° C. till pH ˜9 and then the organiclayer was separated. The organic layer was dried, filtered andevaporated to afford4-chloro-6-methoxy-7-(3-piperidylpropoxy)quinoline-3-carbonitrile as atan solid (0.377 g, 73%). MS(ES) 360.1 (M+H)

Step B: Preparation of{4-[3-cyano-6-methoxy-7-(3-piperidylpropoxy)quinolin-4-yl)piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

To the DMF solution (3 mL) of the 4-chloroquinoline (0.175 g, 0.487mmol) from step A added K2CO3 (0.155 g, 1.10 mmol) followed byN-[4-(methylethoxy)phenyl]piperazinylcarboxamide hydrochloride (0.169 g,0.535 mmol). The reaction mixture was heated to 40° C. overnight, duringthat period starting materials were consumed. After cooling diluted withEtOAc/water and the layers were separated. The organic layer was dried,filtered and evaporated to afford desired product as a crude residue.The crude residue was purified by RP-HPLC to afford{4-[3-cyano-6-methoxy-7-(3-piperidylpropoxy)quinolin-4-yl)piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamideas the desired product (0.195 g, 69%). MS(ES) 587.3 (M+H)

EXAMPLE 2

Preparation ofN-(4-cyanophenyl)[4-[3-cyano-6-methoxy-7-(3-piperidypropoxy)quinolin-4-yl]piperazinyl}carboxamide

To the DMF solution (2 mL) of4-chloro-6-methoxy-7-(3-piperidylpropoxy)quinoline-3-carbonitrile (0.125g, 0.348 mmol) added K2CO3 (0.144 g, 1.04 mmol) followed byN-[4-cyanophenyl]piperazinylcarboxamide (0.11 g, 0.415 mmol) and thereaction was heated at 65° C. overnight. The solvent was evaporated andthe residue purified by RP-HPLC to afford desired productN-(4-cyanophenyl)[4-[3-cyano-6-methoxy-7-(3-piperidypropoxy)quinolin-4-yl]piperazinyl}carboxamideas yellow fluffy solid (90 mg, 50%). MS(ES) 554 (M+H).

EXAMPLE 3

Preparation of{4-[3-ethylcarboxylate-6-methoxy-7-(3-piperidylpropoxy)quinolin-4-yl)piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

The starting material was prepared as follows:

Step A: Preparation of4-chloro-6-methoxy-7-(3-piperidylpropoxy)quinoline-3-carboxylic AcidEthyl Ester

A slurry of4-hydroxy-6-methoxy-7-(3-piperidylpropoxy)quinoline-3-carbonitrile(0.700 g, 1.45 mmol) was refluxed in 6N HCl for 18 h to afford4-hydroxy-6-methoxy-7-(3-piperidylpropoxy)quinoline-3-carboxylic acid.This was dissolved in ethanol (5 mL) and to it added thionyl chloride (1mL) and reaction was heated at 60° C. overnight to4-hydroxy-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinoline-3-carboxylicacid ethyl ester as a viscous oil (0.500 g). The above intermediate wassuspended in SOCl₂ (5 mL) was treated with 0.400 mL of DMF. This mixturewas heated at 90° C. for 30 min during that time all the startingmaterial was consumed by HPLC. The solvent was evaporated in vacuo andthen azetroped with toluene to remove excess thionyl chloride. Theresidue was suspended in H2O/CH2Cl2 (1:1) to this added 20% K₂CO₃ at−10° C. till pH ˜9 and then the organic layer was separated. The organiclayer was dried, filtered and evaporated to afford4-chloro-6-methoxy-7-(3-piperidylpropoxy)quinoline-3-carboxylic acidethyl ester as a tan solid (0.377 g, 73%). MS(ES) 407 (M+H)

Step B: Preparation of4-{4-(4-Isopropoxy-phenylcarbamoyl)-piperazin-1-yl]-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-carboxylicAcid Ethyl Ester

To the DMF solution (3 mL) of the 4-chloroquinoline (0.175 g, 0.487mmol) from step A added K2CO3 (0.155 g, 1.10 mmol) followed byN-[4-(methylethoxy)phenyl]piperazinylcarboxamide hydrochloride (0.169 g,0.535 mmol). The reaction mixture was heated to 40° C. overnight, duringthat period starting materials were consumed. After cooling diluted withEtOAc/water and the layers were separated. The organic layer was dried,filtered and evaporated to afford desired product as a crude residue.The crude residue was purified by RP-HPLC to afford4-{4-(4-Isopropoxy-phenylcarbamoyl)piperazin-1-yl]-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-carboxylicacid ethyl ester (0.170 g, 50%). MS(ES) 634 (M+H)

EXAMPLE 4

Preparation of4-[3-Fluoro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicAcid(4-isopropoxyphenyl)amide

The starting material was prepared as follows:Step A: Preparation of4-chloro-3-Fluoro-6-methoxy-7-(3-piperidylpropoxy)quinoline

Step 1

4-chloro-6-methoxy-7-(3-piperidylpropoxy)quinoline-3-carboxylic Acid (1g)was suspended in DMF (10 ml) with stirring under nitrogen atmosphere,tBuOH (4 ml) was added followed by thiethylamine (3.1 ml) and thendiphenylphosphorylazide (2.5ml) was added. The reaction was then heatedto 100° C. for 8 hrs with stirring under nitrogen atmosphere. Thesolvent was evaporated and extracted the crude product withdichloromethane. The desired product was isolated after flashchromatography eluting with 2%methanol in dichloromethane to give[4-chloro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-yl]-carbamicacid tert-butylester (2.1 g, 65%)

Step 2

[4-chloro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-yl]-carbamicacid tert-butylester (1.8 g) was dissolved in dichloromethane and addedtrifluoroacetic acid (2 ml) and stirred at room temperature for 2 h.This was carefully basified with ammonium hydroxide solution andextracted the desired amino product with ethyl acetate. The solvent wasevaporated to give4-chloro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-ylamine(0.500 g). MS(ES) 350 (M+H).

Step 3

4-chloro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-ylamine(0.300 g) was dissolved in THF (5 ml) with stirring and then cooled inice-water bath to below 0° C., to this added 48% aqueous fluoboric acid(0.7 ml) and mixture stirred for 10 mins. A solution of sodium nitrite(0.10 sg) in water (1 ml) was added keeping the temperature below 10° C.The reaction mixture was the stirred for 1 hr, during that time yellowsolid precipitated. This solid was filtered, dried to give4-chloro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-diazoniumtetrafluoroborate (0.250 g, 80%)

Step 4

4-chloro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-diazoniumtetrafluoroborate (0.200 g) was carefully heated to 150° C., wheredecomposition takes place with gas evolution. After gas evolutionceased, the reaction was cooled and the residue purified by flashchromatography eluting with dichloromethane/methanol 98:2 to4-chloro-3-fluoro-6-methoxy-7-(3-piperidin-1-yl-propoxy)quinoline (0.090g, 30%). MS(ES) 353 (M+H)

Step B: Preparation of4-[3-Fluoro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicAcid(4-isopropoxyphenyl)amide

To the DMF solution (3 mL) of the 4-chloroquinoline (0.070 g, 0.2 mmol)from step 4 added K2CO3 (0.055 g, 0.3 mmol) followed byN-[4-(methylethoxy)phenyl]piperazinylcarboxamide hydrochloride (0.080 g,0.235 mmol). The reaction mixture was heated to 40° C. overnight, duringthat period starting materials were consumed. After cooling diluted withEtOAc/water and the layers were separated. The organic layer was dried,filtered and evaporated to afford desired product as a crude residue.The crude residue was purified by RP-HPLC to afford4-[3-Fluoro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid(4-isopropoxyphenyl)amide (0.100 g, 79%). MS(ES) 634 (M+H). Thesolvent was evaporated in vacuo and then azetroped with toluene toremove excess thionyl chloride. The residue was suspended in H2O/CH2Cl2(1:1) to this added 20% K₂CO₃ at −10° C. till pH ˜9 and then the organiclayer was separated. The organic layer was dried, filtered andevaporated to afford4-chloro-6-methoxy-7-(3-piperidylpropoxy)quinoline-3-carboxylic acidethyl ester as a tan solid (0.377 g, 73%). MS(ES) 407 (M+H)

Step B: Preparation of4-{4-(4-Isopropoxy-phenylcarbamoyl)-piperazin-1-yl]-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-carboxylicAcid Ethyl Ester

To the DMF solution (3 mL) of the 4-chloroquinoline (0.175 g, 0.487mmol) from step A added K2CO3 (0.155 g, 1.10 mmol) followed byN-[4-(methylethoxy)phenyl]piperazinylcarboxamide hydrochloride (0.169 g,0.535 mmol). The reaction mixture was heated to 40° C. overnight, duringthat period starting materials were consumed. After cooling diluted withEtOAc/water and the layers were separated. The organic layer was dried,filtered and evaporated to afford desired product as a crude residue.The crude residue was purified by RP-HPLC to afford4-}4-(4-Isopropoxy-phenylcarbamoyl)piperazin-1-yl]-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-carboxylicacid ethyl ester (0.170 g, 50%). MS(ES) 580 (M+H)

The pharmacological activities of the compounds of the present inventionare obtained by following the test example procedures as follows, forexample.

Biological Test Assay Type I

Inhibitory Effect on Compounds on Autophosphorylation of PlateletDerived Growth Factor β-PDGF Receptor

-   (1) HR5 Phosphorylation Assay

The HR5 cell line is a cell line of CHO cells engineered to overexpresshuman β-PDGFR, which cell line is available from the ATCC. Theexpression level of β-PDGFR in HR5 cells is around 5×10⁴ receptor percell. For the phosphorylation assay according to the invention, HR5cells were grown to confluency in 96-well microtiter plates understandard tissue culture conditions, followed by serum-starvation for 16hours. Quiescent cells were incubated at 37° C. without or withincreasing concentrations of the test compound (0.01-30 uM) for 30minutes followed by the addition of 8 nM PDGF BB for 10 minutes. Cellswere lysed in 100 mM Tris, pH 7.5, 750 mM NaCl, 0.5% Triton X-100, 10 mMsodium pyrophosphate, 50 mM NaF, 10 ug/ml aprotinin, 10 ug/ml leupeptin,1 mM phenylmethylsulfonyl fluoride, 1 mM sodium vanadate, and the lysatewas cleared by centrifugation at 15,000× g for 5 minutes. Clarifiedlysates were transferred into a second microtiter plate in which thewells were previously coated with 500 ng/well of 1B5B11 anti-β-PDGFRmAb, and then incubated for two hours at room temperature. After washingthree times with binding buffer (0.3% gelatin, 25 mM Hepes pH 7.5, 100mM NaCl, 0.01% Tween-20), 250 ng/ml of rabbit polyclonalanti-phosphotyrosine antibody (Transduction Laboratory) was added andplates were incubated at 37° C. for 60 minutes. Subsequently, each wellwas washed three times with binding buffer and incubated with 1 ug/ml ofhorse radish peroxidase-conjugated anti-rabbit antibody (BoehringerMannheim) at 37° C. for 60 minutes. Wells were washed prior to addingABTS (Sigma), and the rate of substrate formation was monitored at 650nm. The assay results are reported as IC₅₀ (expressed as theconcentration of a compound according to the invention that inhibits thePDGF receptor phosphorylation by 50%) as compared to control cells thatare not exposed to a compound according to the invention.

-   (2) MG63 Phosphorylation Assay

The MG63 cell line is a human osteosarcoma tumor cell line availablefrom the ATCC. This assay is for measuring endogenous β-PDGFRphosphorylation in MG63 cells. The assay conditions are the same asthose described at for HR5 cell, except that PDGF-BB stimulation isprovided in the presence or absence of 45% human plasma. The HR5 assayresults are reported as an IC₅₀ (expressed as the concentration of acompound according to the invention that inhibits the PDGF receptorphosphorylation by 50%) as compared to control cells that are notexposed to a compound according to the invention. Examples of such IC₅₀results in the MG63 assay for compounds according to the invention areset forth below in the Table 1.

TABLE 1 MG63 w/human plasma HR5 Example IC₅₀(μM) IC₅₀(μM) Example 10.134 0.060 Example 2 0.103 0.085Biological Test Assay Type 2Growth Inhibition Against Smooth Muscle Cells

Vascular smooth muscle cells are isolated from a pig aorta byexplanation and used for the test. The cells are put into wells of a96-well plate (8000 cells/well) and cultured in Dulbeccois modifiedEagle's medium (DMEM; Nissui Pharmaceutical Co., Ltd.) containing 10%fetal bovine serum (FBS; Hyclone) for 4 days. Then, the cells arefurther cultured in DMEM containing 0.1% FBS for 3 days, and aresynchronized at the cell growth stationary phase.

To each well is added DMEM containing 0.1% FBS and a test sample at avaried concentration, and the cell growth is brought about by PDGF-BB(SIGMA, final concentration: 20 ng/ml). After culturing for 3 days, thecell growth is measured using a cell growth assay kit (BoehringerMannheim) according to the XTT method [J. Immunol. Methods, 142, 257-265(1991)], and the cell growth score is calculated by the followingequation.

Cell growth score=100×{1-(M-PO)/(P100-PO)} wherein P100=absorbance byXTT reagent when stimulated by PDGF-BB; PO=absorbance by XTT reagentwhen not stimulated by PDGF-BB, and M=absorbance by XTT reagent afteraddition of a sample when stimulated by PDGF-BB.

The test result is expressed as the concentration of a test compoundwhich inhibits the cell growth by 50% (IC50).

Biological Test Assay Type 3

Inhibitory Effect on Hypertrophy of Vascular Intima

Male SD rats (weight: 375-445 g, Charles River, golden standard) areanesthetized with sodium pentobarbital (50 mg/kg, i.p.), and then theneck of each animal is incised by the median incision, followed byretrograde insertion of a balloon catheter (2F, Edwards Laboratories)into the left external carotid. After the above treatment is repeatedseven times, the catheter is pulled out, the left external carotid isligated, and the wound is sutured. A test compound is suspended in a0.5% solution of Tween 80 in an aqueous solution of sodium chloride to aconcentration of 20 mg/ml in the case of intraperitoneal administrationand in a 0.5% solution of methyl cellulose 400 to a concentration of 6mg/ml in the case of oral administration. The suspension is administeredonce a day in the case of intraperitoneal administration and once ortwice a day in the case of oral administration for a period of 15 daysstarting on the day before the balloon injury. On the 14th day after theballoon injury, the animal is killed and its left carotid is extirpated.The tissues are fixed with formalin, wrapped in paraffin and sliced,followed by Elastica Wangeeson staining. The area of the cross sectionof the vascular tissues (intima and media) is measured with an imageanalyzer (Luzex F, NIRECO) and the intima/media area ratio (I/M) isregarded as the degree of hypertrophy of the vascular intima.

From the results obtained, it is apparent when the hypertrophy ofvascular intima is significantly inhibited by administration of thecompounds of the present invention.

Biological Test Assay Type 4

Evaluation by the Use of a Rat Adjuvant Arthritis Model

Dead cells of Mycobacterium bacterium (Difco Laboratories Inc.) aredisrupted in agate mortar and suspended in liquid paraffin to the finalconcentration of 6.6 mg/ml, followed by sterilization with high pressuresteam. Then, 100 ml of the suspension is subcutaneously injected intothe right hind foot pad of each animal of groups of female 8-weeks-oldLewis rats (Charles River Japan) (6 animals/group) to induce adjuvantarthritis. A test compound is suspended in a 0.5% solution of methylcellulose to the final concentration of 3 mg/ml, and from just beforethe induction of arthritis, the suspension is orally administered in anamount of 100 ml/100 g of the body weight once a day, 5 days a week. Toa control group is administered a 0.5% solution of methyl cellulose. Anormal group is given no adjuvant treatment or test compoundadministration. The administration of the test compound is continuedtill the 18th day after the adjuvant treatment. On the 17th day, thenumber of leukocytes in peripheral blood are counted, and on the 18thday, all the blood is collected, followed by dissection.

The change in body weight with the passage of time, the change of edemain hind foot with the passage of time, the weight of spleen and thymus,the number of leukocytes in peripheral blood, the hydroxyproline contentof urine, the glucosaminoglycan content of urine, the SH concentrationin serum, the concentration of nitrogen monoxide in serum and theconcentration of mucoprotein in serum are measured and evaluated. Thevolume of each of both hind feet are measured using a rat's hind footedema measurement device (TK-101, Unicom). The number of leukocytes inperipheral blood are counted using an automatic multichannel blood cellcounter (Sysmex K-2000, Toa Iyo Denshi Co., Ltd.). The hydroxyprolinecontent of urine is measured according to the method described in Ikeda,et al., Annual Report of Tokyo Metropolitan Research Laboratories P. H.,36, 277 (1985), and the glucosaminoglycan content is measured accordingto the method described in Moriyama, et al., Hinyo Kiyo, 40, 565 (1994)and Klompmakers, et al., Analytical Biochemistry, 153, 80 (1986). The SHconcentration in serum is measured according to the method described inMiesel, et al., Inflammation, 17, 595 (1993), and the concentration ofnitrogen monoxide is measured according to the method of Tracey, et al.,Journal of Pharmacology & Experimental Therapeutics, 272, 1011 (1995).The concentration of mucoprotein is measured using Aspro GP Kit (OtsukaPharmaceutical Co., Ltd.). The percentage inhibition for each indicationis calculated according to the following equation.% Inhibition={(Control group−Compound-administered group)/(Controlgroup−Normal group)}×100.

From the results obtain from such assays, it is apparent when thecompound according to the invention inhibits the occurrence of adjuvantarthritis.

Biological Test Assay Type 5

Activity on a Mesangial Proliferative Glomerulonephritis Model

Anti-rat Thy-1.1 monoclonal antibody OX-7 (Sedaren) is administered tomale Wister-Kyoto rats (Charles River Japan, 160 g, 6 animals/group) inan amount of 1.0 mg/kg by intravenous administration through the tailvein. A test compound is suspended in a 0.5% solution of methylcelluloseand the resulting suspension is administered to each of the rats twice aday for a period of 7 days starting on the day before the administrationof OX-7. On the 7th day after the OX-7 administration, when mesangialcell growth and extracellular matrix hypertrophy become prominent, theleft kidney of each rat is extirpated, fixed with 20% buffered formalinfor 6 hours and wrapped in paraffin, followed by slicing. The obtainedpieces are subjected to immune tissue staining using antibody PC10(DAKO) against an intranuclear antigen of proliferative cells. Aftercomparative staining with Methyl Green staining solution usingdiaminobenzidine as a color developer, the paraffin pieces are enclosed.Half of the glomeruli in a kidney piece are observed and the number ofthe cells in one glomerulus which are positive to the intranuclearantigen of proliferative cells are calculated. The test for thesignificance of difference is carried out by the Wilcoxon test.

From such results, it is apparent when the compounds according to thepresent invention show alleviating activity on mesangial proliferativeglomerulonephritis.

The compounds of formula (I) and formula (Ia) and pharmaceuticallyacceptable salts thereof can be administered as such, but it is usuallypreferred to administer them in the form of pharmaceutical compositions,which are used for animals and human beings.

It is preferred to employ the administration route which is the mosteffective for the treatment. For example, administration is made orallyor non-orally by intrarectal, intraoral, subcutaneous, intramuscular orintravenous administration.

Examples of the forms for administration are capsules, tablets,granules, powders, syrups, emulsions, suppositories and injections.

Liquid compositions such as emulsions and syrups which are appropriatefor oral administration can be prepared using water, sugars such assucrose, sorbitol and fructose, glycols such as polyethylene glycol andpropylene glycol, oils such as sesame oil, olive oil and soybean oil,preservatives such as benzoates, flavors such as strawberry flavor andpeppermint, etc.

Capsules, tablets, powders and granules can be prepared using excipientssuch as lactose, glucose, sucrose and mannitol, disintegrating agentssuch as starch and sodium alginate, lubricants such as magnesiumstearate and talc, binders such as polyvinyl alcohol, hydroxypropylcellulose and gelatin, surfactants such as fatty acid esters,plasticizers such as glycerin, etc.

Compositions suitable for non-oral administration preferably comprise asterilized aqueous preparation containing an active compound which isisotonic to the recipient's blood. For example, injections are preparedusing a carrier which comprises a salt solution, a glucose solution, ora mixture of a salt solution and a glucose solution.

Compositions for topical application are prepared by dissolving orsuspending an active compound in one or more kinds of solvents such asmineral oil, petroleum and polyhydric alcohol, or other bases used fortopical drugs.

Compositions for intestinal administration are prepared using ordinarycarriers such as cacao fat, hydrogenated fat and hydrogenated fatcarboxylic acid, and are provided as suppositories.

The compositions for non-oral administration may additionally beformulated to contain one or more kinds of additives selected fromglycols, oils, flavors, preservatives (including antioxidants),excipients, disintegrating agents, lubricants, binders, surfactants andplasticizers which are used for the preparation of compositions for oraladministration.

The effective dose and the administration schedule for each of thecompounds of formula (I) or a pharmaceutically acceptable salt thereofwill vary depending on the administration route, the patient's age andbody weight, and the type or degree of the diseases to be treated.However, it is generally appropriate to administer a compound of formula(I) or a pharmaceutically acceptable salt thereof in a dose of 0.01-1000mg/adult/day, preferably 5-500 mg/adult/day, in one to several parts.

All the compounds of the present invention can be immediately applied tothe treatment of kinase-dependent diseases of mammals as kinaseinhibitors, specifically, those relating to tyrosine kinase.Specifically preferred are the compounds which have IC₅₀ within therange of 10 nM-10 μM. Even more preferred are compounds which have IC₅₀within the range of 10 nM to −1 μM. Most preferred are compounds whichhave an IC₅₀ value which is less than 1 μM.

Specific compounds of the present invention which have an activity tospecifically inhibit one of the three types of protein kinase (forexample, kinase which phosphorylates tyrosine, kinase whichphosphorylates tyrosine and threonine, and kinase which phosphorylatesthreonine) can be selected. Tyrosine kinase-dependent diseases includehyperproliferative malfunction which is caused or maintained by abnormaltyrosine kinase activity. Examples thereof include psoriasis, pulmonaryfibrosis, glomerulonephritis, cancer, atherosclerosis andanti-angiopoiesis (for example, tumor growth and diabetic retinopathy).Current knowledge of the relationship between other classes of kinaseand specific diseases is insufficient. However, compounds havingspecific PTK-inhibiting activity have a useful treatment effect. Otherclasses of kinase have also been recognized in the same manner.Quercetin, genistein and staurosporin, which are all PTK-inhibitors,inhibit many kinds of protein kinase in addition to tyrosine kinase.However, as a result of their lack of the specificity, theircytotoxicity is high. Therefore, a PTK-inhibitor (or an inhibitor ofother classes of kinase) which is apt to bring about undesirable sideeffects because of the lack of selectivity can be identified by the useof an ordinary test to measure cytotoxicity.

The term “effective amount” is an amount necessary for administering thecompound in accordance with the present invention to provide thenecessary effect such as inhibiting the phosphorylation of kinases ortreating disease states in a mammal. In accordance with the presentinvention, a suitable single dose size is a dose that is capable ofpreventing or treating an animal with a disease when administered one ormore times over a suitable time period. Doses can vary depending uponthe disease being treated. For example, in the treatment ofhypersensitivity, a suitable single dose can be dependent upon thenature of the immunogen causing the hypersensitivity.

The “effective amount” of the compound of the present invention canrange broadly depending upon the desired affects and the therapeuticindication. Typically, dosages will be between about 0.01 mg/kg and 100mg/kg body weight, preferably between about 0.01 and 10 mg/kg, bodyweight.

“Pharmaceutically acceptable carriers” for therapeutic use are wellknown in the pharmaceutical art, and are described, for example, inRemingtons Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaroedit. 1985). For example, sterile saline and phosphate-buffered salineat physiological pH may be used. Preservatives, stabilizers, dyes andeven flavoring agents may be provided in the pharmaceutical composition.For example, sodium benzoate, sorbic acid and esters of p-hydroxybenzoicacid may be added as preservatives. In addition, antioxidants andsuspending agents may be used.

In the compounds of this invention, carbon atoms bonded to fournon-identical substituents are asymmetric. Accordingly, the compoundsmay exist as diastereoisomers, enantiomers or mixtures thereof. Thesyntheses described herein may employ racemates, enantiomers ordiastereomers as starting materials or intermediates. Diastereomericproducts resulting from such syntheses may be separated bychromatographic or crystallization methods, or by other methods known inthe art. Likewise, enantiomeric product mixtures may be separated usingthe same techniques or by other methods known in the art. Each of theasymmetric carbon atoms, when present in the compounds of thisinvention, may be in one of two configurations (R or S) and both arewithin the scope of the present invention.

Prodrug Derivatives of Compounds

This invention also encompasses prodrug derivatives of the compoundscontained herein. The term “prodrug” refers to a pharmacologicallyinactive derivative of a parent drug molecule that requiresbiotransformation, either spontaneous or enzymatic, within the organismto release the active drug. Prodrugs are variations or derivatives ofthe compounds of this invention which have groups cleavable undermetabolic conditions. Prodrugs become the compounds of the inventionwhich are pharmaceutically active in vivo, when they undergo solvolysisunder physiological conditions or undergo enzymatic degradation. Prodrugcompounds of this invention may be called single, double, triple etc.,depending on the number of biotransformation steps required to releasethe active drug within the organism, and indicating the number offunctionalities present in a precursor-type form. Prodrug forms oftenoffer advantages of solubility, tissue compatibility, or delayed releasein the mammalian organism (see, Bundgard, Design of Prodrugs, pp. 7-9,21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry ofDrug Design and Drug Action, pp. 352-401, Academic Press, San Diego,Calif., 1992). Prodrugs commonly known in the art include acidderivatives well known to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acids with a suitablealcohol, or amides prepared by reaction of the parent acid compound withan amine, or basic groups reacted to form an acylated base derivative.Moreover, the prodrug derivatives of this invention may be combined withother features herein taught to enhance bioavailability.

Formulations of the compounds of this invention are prepared for storageor administration by mixing the compound having a desired degree ofpurity with physiologically acceptable carriers, excipients, stabilizersetc., and may be provided in sustained release or timed releaseformulations. Acceptable carriers or diluents for therapeutic use arewell known in the pharmaceutical field, and are described, for example,in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A. R.Gennaro edit. 1985). Such materials are nontoxic to the recipients atthe dosages and concentrations employed, and include buffers such asphosphate, citrate, acetate and other organic acid salts, antioxidantssuch as ascorbic acid, low molecular weight (less than about tenresidues) peptides such as polyarginine, proteins, such as serumalbumin, gelatin, or immunoglobulins, hydrophilic polymers such aspolyvinylpytrolidinone, amino acids such as glycine, glutamic acid,aspartic acid, or arginine, monosaccharides, disaccharides, and othercarbohydrates including cellulose or its derivatives, glucose, mannoseor dextrins, chelating agents such as EDTA, sugar alcohols such asmannitol or sorbitol, counterions such as sodium and/or nonionicsurfactants such as Tween, Pluronics or polyethyleneglycol.

An effective administration protocol (i.e., administering a therapeuticcomposition in an effective manner) comprises suitable dose parametersand modes of administration that result in prevention or treatment of adisease. Effective dose parameters and modes of administration can bedetermined using methods standard in the art for a particular disease.Such methods include, for example, determination of survival rates, sideeffects (i.e., toxicity) and progression or regression of disease. Forexample, the effectiveness of dose parameters and modes ofadministration of a therapeutic composition of the present invention canbe determined by assessing response rates. Such response rates refer tothe percentage of treated patients in a population of patients thatrespond with either partial or complete remission.

Dosage formulations of the compounds of the invention to be used fortherapeutic administration must be sterile. Sterility is readilyaccomplished by filtration through sterile membranes such as 0.2 micronmembranes, or by other conventional methods. Formulations typically willbe stored in lyophilized form or as an aqueous solution. The pH of thepreparations of the invention typically will be about 3-11, morepreferably about 5-9 and most preferably about 7-8. It will beunderstood that use of certain of the foregoing excipients, carriers, orstabilizers will result in the formation of cyclic polypeptide salts.While the preferred route of administration is by injection, othermethods of administration are also anticipated such as orally,intravenously (bolus and/or infusion), subcutaneously, intramuscularly,colonically, rectally, nasally, transdermally or intraperitoneally,employing a variety of dosage forms such as suppositories, implantedpellets or small cylinders, aerosols, oral dosage formulations andtopical formulations such as ointments, drops and dermal patches. Thecompounds of the invention are desirably incorporated into shapedarticles such as implants which may employ inert materials such asbiodegradable polymers or synthetic silicones, for example, Silastic,silicone rubber or other polymers commercially available.

The compounds of the invention may also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of lipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds of the invention may also be delivered by the use ofantibodies, antibody fragments, growth factors, hormones, or othertargeting moieties, to which the compound molecules are coupled. Thecompounds of the invention may also be coupled with suitable polymers astargetable drug carriers. Such polymers can includepolyvinylpyrrolidinone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinewith palmitoyl residues. Furthermore, compounds of the invention may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example polylactic acid, polyglycolicacid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross linked or amphipathicblock copolymers of hydrogels. Polymers and semipermeable polymermatrices may be formed into shaped articles, such as valves, stents,tubing, prostheses and the like.

Therapeutic compound liquid formulations generally are placed into acontainer having a sterile access port, for example, an intravenoussolution bag or vial having a stopper pierceable by hypodermic injectionneedle.

Therapeutically effective dosages may be determined by either in vitroor in vivo methods. For each particular compound of the presentinvention, individual determinations may be made to determine theoptimal dosage required. The range of therapeutically effective dosageswill be influenced by the route of administration, the therapeuticobjectives and the condition of the patient. For injection by hypodermicneedle, it may be assumed the dosage is delivered into the body'sfluids. For other routes of administration, the absorption efficiencymust be individually determined for each compound by methods well knownin pharmacology. Accordingly, it may be necessary for the therapist totiter the dosage and modify the route of administration as required toobtain the optimal therapeutic effect. The determination of effectivedosage levels, that is, the dosage levels necessary to achieve thedesired result, will be readily determined by one skilled in the art.Typically, applications of compound are commenced at lower dosagelevels, with dosage levels being increased until the desired effect isachieved.

The compounds and compositions of the invention can be administeredorally or parenterally in an effective amount within the dosage range ofabout 0.001 to about 1000 mg/kg, preferably about 0.01 to about 100mg/kg and more preferably about 0.1 to about 20 mg/kg. Advantageously,the compounds and composition of the invention may be administeredseveral times daily. Other dosage regimens may also be useful (e.g.single daily dose and/or continuous infusion).

Typically, about 0.5 to about 500 mg of a compound or mixture ofcompounds of the invention, as the free acid or base form or as apharmaceutically acceptable salt, is compounded with a physiologicallyacceptable vehicle, carrier, excipient, binder, preservative,stabilizer, dye, flavor etc., as called for by accepted pharmaceuticalpractice. The amount of active ingredient in these compositions is suchthat a suitable dosage in the range indicated is obtained.

Typical adjuvants which may be incorporated into tablets, capsules andthe like are binders such as acacia, corn starch or gelatin, andexcipients such as microcrystalline cellulose, disintegrating agentslike corn starch or alginic acid, lubricants such as magnesium stearate,sweetening agents such as sucrose or lactose, or flavoring agents. Whena dosage form is a capsule, in addition to the above materials it mayalso contain liquid carriers such as water, saline, or a fatty oil.Other materials of various types may be used as coatings or as modifiersof the physical form of the dosage unit. Sterile compositions forinjection can be formulated according to conventional pharmaceuticalpractice. For example, dissolution or suspension of the active compoundin a vehicle such as an oil or a synthetic fatty vehicle like ethyloleate, or into a liposome may be desired. Buffers, preservatives,antioxidants and the like can be incorporated according to acceptedpharmaceutical practice.

Acid addition salts include hydrochlorides, hydrobromides, hydrolodides,alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, orisethionates, arylsulphonates, e.g. p-toluenesulphonates, besylates ornapsylates, phosphates, sulphates, hydrogen sulphates, acetates,trifluoroacetates, propionates, citrates, maleates, fumarates,malonates, succinates, lactates, oxalates, tartrates and benzoates.Salts derived from inorganic or organic bases include alkali metal saltssuch as sodium or potassium salts, alkaline earth metal salts such asmagnesium or calcium salts, and organic amine salts such as morpholine,piperidine, dimethylamine or diethylamine salts. Prodrugs of compoundsof formula (1) include those compounds, for example esters, alcohols oraminos, which are convertible in vivo by metabolic means, e.g. byhydrolysis, reduction, oxidation or transesterification, to compounds offormula (1). Particularly useful salts of compounds according to theinvention include pharmaceutically acceptable salts, especially acidaddition pharmaceutically acceptable salts. Next, the pharmacologicalactivity of the compounds of the present invention are specificallyexplained by test examples.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the illustrativeexamples, make and utilize the compounds of the present invention andpractice the claimed methods. It should be understood that the foregoingdiscussion and examples merely present a detailed description of certainpreferred embodiments. The examples given above are non-limiting in thatone of ordinary skill in view of the above will readily envision otherpermutations and variations on the invention without departing from theprincipal concepts. Such permutations and variations are also within thescope of the present invention. All the patents, journal articles andother documents discussed or cited above are herein incorporated byreference. The invention is further illustrated with reference to theclaims that follow thereto.

1. A compound having the following formula:

wherein: V is O or S; X is —(CH₂)₁₋₂—OH, —CH₂—C(═O)—O(—CH₂)₀₋₈—CH₃,—CH₂—C(═O)—H, or (—CH₂)₀₋₁—CN, F or Cl; Y is —CN, —Br, —CF₃, —O—C₁₋₈alkyl that is independently straight or branched chained, —O-phenyl,—O-naphthyl, —O-indolyl or —O-isoquinolinyl; R² and R⁴ are eachindependently a member selected from the group consisting of: —O—CH₃,—O(—CH₂)—CH₃, —O—CH₂—CH═CH₂, —O—CH₂—C≡CH and —O(—CH₂)₂₋₃—R^(2a); R^(2a)is a member selected from the group consisting of: —OH, —O—CH₃,—O—CH₂—CH₃, —NH₂, —N(—CH₃)₂, —NH(—CH₂-Phenyl), —NH(-Phenyl), —CN,

or all pharmaceutically acceptable salts or hydrates thereof.
 2. Acompound of claim 1 wherein: V is O or S; X is CN, F or Cl; Y is —CN,—O—C₁₋₈ alkyl that is independently straight or branched chained,—O-phenyl, —O-naphthyl, —O-indolyl or —O-isoquinolinyl; R² and R⁴ areeach different and independently a member selected from the groupconsisting of: —O—(CH₂—)₀₋₁—CH₃ and —O(—CH₂)₂₋₃—R^(2a); R^(2a) is amember selected from the group consisting of:

or all pharmaceutically acceptable salts or hydrates thereof.
 3. Acompound of claim 1 selected from the group consisting of:N-(4-indol-5-yloxyphenyl){4-[3-cyano-6-methoxy-7-(2-methoxyothoxy)quinolin-4-yl]piperazinyl}carboxamide

N-(4-indol-4yloxyphenyl){4-[3-cyano-6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl]piperazinyl}carboxamide

{4-[3-cyano-6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]piperazinyl}-N-(4-naphthyloxyphenyl)carboxamide

{4-[3-cyano-6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl]piperazinyl}-N-(4-(2-naphthyloxy)phenyl)carboxamide

N-(4-(5-isoquinolyloxy)phenyl){4-[3-cyano-6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl]piperazinyl}carboxamide

{4-[3-cyano-6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl]piperazinyl}-N-(4-phenoxyphenyl)carboxamide

{4-[3-cyano-6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl){4-[3-cyano-6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl]piperazinyl}carboxamide

{4-[3-cyano-6-methoxy-7-(2-piperidylethoxy)quinolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl){4-[3-cyano-6-methoxy-7-(2-piperidylethoxy)quinolin-4-yl]piperazinyl}carboxamide

{4-[3-cyano-6-methoxy-7-(3-piperidylpropoxy)quinolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

{4-[3-cyano-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl){4-[3-cyano-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]piperazinyl}carboxamide

{4-[3-cyano-6-methoxy-7-(3-pyrrolidinylpropoxy)quinolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl){4-[3-cyano-6-methoxy-7-(2-(1,2,3,4-tetraazol-2-yl)ethoxy)quinolin-4-yl]piperazinyl}carboxamide

N-(4-cyanophenyl){4-[3-cyano-6-methoxy-7-(2-(1,2,3,4-tetraazolyl)ethoxy)quinolin-4-yl]piperazinyl}carboxamide

{4-(3-cyano-6-methoxy-7(2-(1,2,3,4-tetraazolyl)ethoxy)quinolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

{4-[3-cyano-6-methoxy-7-(2-(1,2,3,4-tetraazol-2-yl)ethoxy)quinolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

(4-{3-cyano-7-(3-(4,4-difluoropiperidyl)propoxy)-6-methoxyquinolin-4-yl}piperazinyl)-N-[4-(methylethoxy)phenyl]carboxamide

{4-[3-cyano-6-methoxy-7-(3-piperazinylpropoxy)quinolin-4-yl]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

N-(4-cyanophenyl)(4-{3-cyano-6-methoxy-7-[3-(4-methylpiperazinyl)propoxy]quinolin-4-yl}piperazinyl)carboxamide

N-(4-cyanophenyl){4-[3-cyano-6-methoxy-7-(3-(4-thiazaperhydroin-4-yl)propoxy)quinolin-4-yl]piperazinyl}carboxamide

(4-{3-cyano-7-[3-(1,1-dioxo(1,4-thiazaperhydroin-4-yl))propoxy]-6-methoxyquinolin-4-yl}piperazinyl)-N-(4-cyanophenyl)carboxamide

N-(4-cyanophenyl)[4-(3-cyano-7-ethoxy-6-methoxyquinolin-4-yl)piperazinyl]carboxamide

[4-(3-cyano-7-ethoxy-6-methoxyquinolin-4-yl)piperazinyl]-N-[4-(methylethoxy)phenyl]carboxamide

[4-(3-cyano-7-ethoxy-6-methoxyquinolin-4-yl)piperazinyl]-N-(4-naphthyloxyphenyl)carboxamide

[4-(3-cyano-7-ethoxy-6-methoxyquinolin-4-yl)piperazinyl]-N-(4-indol-4-yloxyphenyl)carboxamide

[4-(-3-cyano-(7-ethoxy-6-methoxyquinolin-4-yl)piperazinyl]-N-(4-phenoxyphenyl)carboxamide

N-(4-cyanophenyl)[4-(3-cyano-6-methoxy-7-prop-2-enyloxyquinolin-4-yl)piperazinyl]carboxamide

[4-(3-cyano-6-methoxy-7-prop-2-enyloxyquinolin-4-yl)piperazinyl]-N-[4-(methylethoxy)phenyl]carboxamide

[4-(3-cyano-6-methoxy-7-prop-2-enyloxyquinolin-4-yl)piperazinyl]-N-(4-naphthyloxyphenyl)carboxamide

N-(4-indol-4-yloxyphenyl)[4-(3-cyano-6-methoxy-7-prop-2-enyloxyquinolin-4-yl)piperazinyl]carboxamide

[4-(3-cyano-6-methoxy-7-prop-2-enyloxyquinolin-4-yl)piperazinyl]-N-(4-phenoxyphenyl)carboxamide

N-(4-cyanophenyl)[4-(3-cyano-6-methoxy-7-prop-2-ynyloxyquinolin-4-yl)piperazinyl]carboxamide

[4-(3-cyano-6-methoxy-7-prop-2-ynyloxyquinolin-4-yl)piperazinyl]-N-[4-(methylethoxy)phenyl]carboxamide

[4-(3-cyano-6-methoxy-7-prop-2-ynyloxyquinolin-4-yl)piperazinyl]-N-(4-naphthyloxyphenyl)carboxamide

N-(4-indol-4-yloxyphenyl)[4-(3-cyano-6-methoxy-7-prop-2-ynyloxyquinolin-4-yl)piperazinyl]carboxamide

[4-(3-cyano-6-methoxy-7-prop-2-ynyloxyquinolin-4-yl)piperazinyl]-N-(4-phenoxyphenyl)carboxamide

ethyl-6-methoxy-4-(4-{N-[4-(methylethoxy)phenyl]carbamoyl}piperazinyl)-7-(3-piperidylpropoxy)quinoline-3-carboxylate

ethyl-6-methoxy-4-(4-{N-[4-(methylethoxy)phenyl]carbamoyl}piperazinyl)-7-(3-morpholin-4-ylpropoxy)quinoline-3-carboxylate

ethyl-6-methoxy-4-(4-{N-[4-(methylethoxy)phenyl]carbamoyl}piperazinyl)-7-(3-(1,2,3-triazolyl)propoxy)quinoline-3-carboxylate

6-methoxy-4-(4-{N-[4-(methylethoxy)phenyl]carbamoyl}piperazinyl)-7-(3-(1,2,3-triazol-2-yl)propoxy)quinoline-3-carboxylic

ethyl-4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-(3-piperidylpropoxy)quinoline-3-carboxylate

ethyl-4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinoline-3-carboxylate

ethyl-4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-(3-pyrrolidinylpropoxy)quinoline-3-carboxylate

ethyl-4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-(3-(1,2,3-triazolyl)propoxy)quinoline-3-carboxylate

ethyl-4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-(3-(1,2,3-triazol-2-yl)propoxy)quinoline-3-carboxylate

ethyl-4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-(3-(1,2,3,4-tetraazol-2-yl)propoxy)quinoline-3-carboxylate

ethyl-4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-(3-(1,2,3,4-tetraazolyl)propoxy)quinoline-3-carboxylate

ethyl-7-[3-(1,1-dioxo(1,4-thiazaperhydroin-4-yl))propoxy]-4-{4-[N-(4-cyano-phenyl)carbomoyl]piperazinyl}-6-methoxyquinoline-3-carboxylate

ethyl-4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-(3-piperazinylpropoxy)quinoline-3-carboxylate

ethyl-4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-(2-methoxyethoxy)quinoline-3-carboxylate

ethyl6-methoxy-7-(2-methoxyethoxy)-4-(4-{N-[4-(methylethoxy)phenyl]-carbamoyl}piperazinyl)quinoline-3-carboxylate

ethyl-4-{4-[N-(4-cyanophenyl)carbamoyl]piperazinyl}-6-methoxy-7-[3-(4-methylpiperazinyl)propoxy]quinoline-3-carboxylate

{4-[3-carbonyl-6-methoxy-7-(3-piperidylpropoxy)(4-quinolyl)]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

{4-[3-carbonyl-6-methoxy-7-(3-morpholin-4-ylpropoxy)(4-quinolyl)]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

(4-{7-[3-(1,1-dioxo(1,4-thiazaperhydroin-4-yl))propoxy]-3-carbonyl-6-methoxy(4-quinolyl)}piperazinyl)-N-[4-(methylethoxy)phenyl]carboxamide

{4-[3-carbonyl-6-methoxy-7-(3-pyrrolidinylpropoxy)(4-quinolyl)]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

{4-[3-carbonyl-6-methoxy-7-(3-piperidylpropoxy)(4-quinolyl)]piperazinyl}-N-(4-cyanophenyl)carboxamide

{4-[3-carbonyl-6-methoxy-7-(3-morpholin-4-ylpropoxy)(4-quinolyl)]piperazinyl}-N-(4-cyanophenyl)carboxamide

{4-[3carbonyl-6-methoxy-7-(3-pyrrolidinylpropoxy)(4-quinolyl)]piperazinyl}-N-(4-cyanophenyl)carboxamide

{4-[3-carbonyl-6-methoxy-7-(3-(1,2,3-triazolyl)propoxy)(4-quinolyl)]piperazinyl}-N-(4-cyanophenyl)carboxamide

{4-[3-carbonyl-6-methoxy-7-(3-(1,2,3-triazol-2-yl)propoxy)(4-quinolyl)]piperazinyl}-N-(4-cyanophenyl)carboxamide

N-(4-cyanophenyl){4-[3-(hydroxymethyl)-6-methoxy-7-(3-piperidylpropoxy)(4-quinolyl)]piperazinyl}carboxamide

N-(4cyanophenyl){4-[3-(hydroxymethyl)-6-methoxy-7-(3-morpholin-4ylpropoxy)(4-quinolyl)]piperazinyl}carboxamide

N-(4-cyanophenyl){4-[3-(hydroxymethyl)-6-methoxy-7-(3-pyrrolidinylpropoxy)(4-quinolyl)]piperazinyl}carboxamide

{4-[3-(hydroxymethyl)-6-methoxy-7-(3-piperidylpropoxy)(4-quinolyl)]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

{4-[3-(hydroxymethyl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)(4-quinolyl)]piperazinyl}-N-4-(methylethoxy)phenyl]carboxamide

(4-{7-[3-(1,1-dioxo(1,4-thiazaperhydroin-4-yl))propoxy]-3-(hydroxymethyl)-6-methoxy(4-quinolyl)}piperazinyl)-N-[4-(methylethoxy)phenyl]carboxamide

{4-[3-(hydroxymethyl)-6-methoxy-7-(3-pyrrolidinylpropoxy)(4-quinolyl)]piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide

4-[3-Aminomethyl-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid (4-cyano-phenyl)-amide

4-[3-Aminomethyl-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid(4-isopropoxy-phenyl)-amide

4-[3-Aminomethyl-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid(4-cyano-phenyl)-amide

4-[3-Aminomethyl-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid (4-isopropoxy-phenyl)-amide

4-[3-Cyano-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid (4-cyano-phenyl)-amide

4-[3-Cyano-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid (4-bromo-phenyl)-amide

4-[3-Cyano-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid (4-isopropoxy-phenyl)-amide

4-({4-[3-Cyano-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carbonyl}-amino)-benzoicacid methyl ester

4-({4-[3-Cyano-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carbonyl}-amino)-benzoicacid methyl ester

4-[3-Cyano-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid (4-bromo-phenyl)-amide

4-[3-Cyano-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid (4-trifluoromethyl-phenyl)-amide

4-[3-Cyano-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid (4-fluoro-phenyl)-amide

4-[3-Fluoro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid (4-cyano-phenyl)-amide

4-[3-Fluoro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid (4-isopropoxy-phenyl)-amide

4-[3-Fluoro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid (4-cyano-phenyl)-amide

4-[3-Fluoro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid (4-isopropoxy-phenyl)-amide

4-[3-Fluoro-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid (4-cyano-phenyl)-amide

4-[3-Fluoro-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid (4-bromo-phenyl)-amide

4-[3-Fluoro-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carboxylicacid (4-isopropoxy-phenyl)-amide

4-({4-[3-Fluoro-6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yl]-piperazine-1-carbonyl}-amino)-benzoicacid methyl ester

or all pharmaceutically acceptable salts or hydrates thereof.
 4. Apharmaceutical composition comprising and effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable diluent or carrier.
 5. A method oftreating a cell-proliferative disease in a patient in need thereof, saidmethod comprising administering to the patient a composition accordingto claim 4 wherein the cell-proliferative disease is selected from thegroup consisting of bone cancer, arteriosclerosis, vascularreobstruction, articular rheumatism, psoriasis, diabetic retinopathy,glomerulonephritis and glomerulosclerosis.